Quinoline derivatives

ABSTRACT

or a pharmaceutically acceptable salt thereof as described herein. The present disclosure also provides pharmaceutical compositions comprising a compound of Formula (I), processes for preparing compounds of Formula (I), and therapeutic methods for treating inflammatory disease.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No.62/752,805, filed Oct. 30, 2018, and U.S. Provisional Application No.62/823,987, filed Mar. 26, 2019, both of which are incorporated hereinin their entireties for all purposes.

FIELD

The present disclosure relates generally to novel compounds that haveα4β7 integrin inhibitory action, prodrugs of compounds having α4β7integrin inhibitory action, and methods of use and manufacture thereof.

BACKGROUND

Integrins are heterodimeric cell surface proteins involved in numerouscellular processes including cell-cell and cell-extracellular matrixinteractions. Upon binding of an extracellular ligand, integrins mediatesignal transduction to the cell interior resulting in lymphocyte cellcapture, adhesion, and infiltration into the tissue.

Integrins are heterodimeric proteins consisting of an alpha and a betasubunit. There are 18 known alpha subunits and 8 known beta subunits.The α4β7 integrin is expressed on the surface of lymphocytes andrecognizes the extracellular ligand mucosal addressing cell adhesionmolecule-1 (MAdCAM-1). α4β7 integrin governs lymphocyte trafficking toand retention in gut tissues through its interaction with MAdCAM-1,which is expressed on venules in the intestinal mucosa and highendothelial venules (HEV) in the gut-associated lymphoid tissues (GALT).Inhibiting the interactions of integrins with their respective ligandshas been proposed as an effective method of treating a variety ofautoimmune and inflammatory diseases, and blocking the α4β7-MAdCAM-1interaction has shown therapeutic benefit in inflammatory bowel disease(Crohn's disease and ulcerative colitis).

There is a need to for improved α4β7 integrin antagonist molecules forthe treatment of autoimmune and inflammatory diseases, includinginflammatory bowel disease.

SUMMARY

The present disclosure provides compounds that are inhibitors for α4β7integrin. The disclosure also provides compositions, includingpharmaceutical compositions, kits that include the compounds, andmethods of using (or administering) and making the compounds. Thecompounds provided herein are useful in treating diseases, disorders, orconditions that are mediated by α4β7 integrin. The disclosure alsoprovides compounds for use in therapy. The disclosure further providescompounds for use in a method of treating a disease, disorder, orcondition that is mediated by α4β7 integrin. Moreover, the disclosureprovides uses of the compounds in the manufacture of a medicament forthe treatment of a disease, disorder or condition that is mediated byα4β7 integrin.

In one aspect, provided is a compound having the structure of Formula(I), or a pharmaceutically acceptable salt thereof:

L is selected from a bond, —O—, —O—C(O)—*, —NH—, —C(O)—N(H)—*, and—N(H)—C(O)—*; wherein * indicates the point of attachment of L to R¹;

R¹ is selected from A¹, A², A³, and A⁴;

-   -   A¹ is 5-10 membered heteroaryl containing one to five        heteroatoms independently selected from S, N, and O; wherein A¹        optionally comprises one to three C(O); and wherein A¹ is        optionally substituted with one to six R^(a);    -   A² is C₆₋₁₀aryl, optionally substituted with one to six R^(a);    -   A³ is C₅₋₁₀cycloalkyl or 5-14 membered heterocyclyl; wherein A³        is optionally substituted with one to four groups independently        selected from oxo and R^(a); and    -   A⁴ is —NR^(a1)R^(a2);        -   wherein each R^(a) is independently selected from halo,            cyano, hydroxyl, —NR^(a1)R^(a2), C₁₋₆alkyl, C₂₋₆alkenyl,            C₂₋₆alkynyl, C₁₋₆alkoxyl, C₁₋₆haloalkyl, C₁₋₆haloalkoxyl,            —S(O)_(m)—C₁₋₆alkyl, C₃₋₈cycloalkyl, 3-6 membered            heterocyclyl, C₆₋₁₀aryl, 5-6 membered heteroaryl,            —O—C₃₋₈cycloalkyl, —O-(3-6 membered heterocyclyl),            —O—C₁₋₄alkylene-C₃₋₈cycloalkyl, and —O-phenyl;            -   wherein each C₃₋₈cycloalkyl, 3-6 membered heterocyclyl,                C₆₋₁₀aryl, 5-6 membered heteroaryl, —O—C₃₋₈cycloalkyl,                —O-(3-6 membered heterocyclyl),                —O—C₁₋₄alkylene-C₃₋₈cycloalkyl, and —O-phenyl of R^(a)                is independently optionally substituted with one to                three groups independently selected from halo, cyano,                hydroxyl, —NR^(a1)R^(a2), C₁₋₆alkyl, C₁₋₆haloalkyl,                C₁₋₆alkoxyl, and C₁₋₆haloalkoxyl; and            -   wherein each C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,                C₁₋₆alkoxyl, C₁₋₆haloalkyl, C₁₋₆haloalkoxyl, and                —S(O)_(m)—C₁₋₆alkyl of R^(a) is optionally substituted                with one to three R^(a3), wherein each R^(a3) is                independently selected from halo, cyano, hydroxyl,                —NR^(a1)R^(a2), C₁₋₆alkoxyl, C₃₋₈cycloalkyl, and 3-6                membered heterocyclyl;            -   wherein each C₃₋₈cycloalkyl and 3-6 membered                heterocyclyl of R^(a3) is optionally substituted with                one to three R^(a4); and each R^(a4) is independently                selected from halo, cyano, hydroxyl, —NR^(a1)R^(a2),                C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxyl, C₁₋₆haloalkoxyl,                C₃₋₈cycloalkyl, and 3-6 membered heterocyclyl;

each R², R³, R⁴, R⁵, and R⁶ is independently selected from H, halo,cyano, hydroxyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxyl,C₁₋₈haloalkyl, C₁₋₈haloalkoxyl, —NR^(b1)R^(b2), —R^(b3)S(O)_(m)R^(b4),—S(O)_(m)R^(b4), —NR^(b1)S(O)_(n)R^(b4), —COOR^(b1), —CONR^(b1)R^(b2),—NR^(b1)COOR^(b2), —NR^(b1)COR^(b4), —R^(b3)NR^(b1)R^(b2),—S(O)_(n)NR^(b1)R^(b2), C₃₋₁₂cycloalkyl, C₆₋₁₀aryl, 5-6 memberedheteroaryl, and 3-12 membered heterocyclyl;

-   -   wherein each C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxyl,        C₁₋₈haloalkyl, and C₁₋₈haloalkoxyl of R², R³, R⁴, R⁵, and R⁶ is        optionally substituted with one to two R^(c); wherein each R^(c)        is independently selected from azido, oxo, cyano, halo,        hydroxyl, —NR^(a1)R^(a2), C₁₋₄alkoxyl, C₃₋₈cycloalkyl,        C₆₋₁₀aryl, 5-6 membered heteroaryl, and 4-6 membered        heterocyclyl; wherein each C₃₋₈cycloalkyl, C₆₋₁₀aryl, 5-6        membered heteroaryl, and 4-6 membered heterocyclyl of R^(c) is        optionally substituted with one to three groups independently        selected from halo, cyano, hydroxyl, —NR^(a1)R^(a2), C₁₋₄alkyl,        C₁₋₆haloalkyl, C₁₋₄alkoxyl, and C₃₋₆cycloalkyl;    -   wherein each C₆₋₁₀aryl, and 5-6 membered heteroaryl of R², R³,        R⁴, R⁵, and R⁶ is independently optionally substituted with one        to five R^(b); and    -   wherein each C₃₋₁₂cycloalkyl, and 3-12 membered heterocyclyl of        R², R³, R⁴, R⁵, and R⁶ is independently optionally substituted        with one to six groups independently selected from        ═CR^(b1)R^(b2) and R^(b);        -   wherein each R^(b) is independently selected from azido,            cyano, halo, hydroxyl, —NR^(a1)R^(a2), C₁₋₆alkyl,            C₁₋₈haloalkyl, C₁₋₆alkoxyl, C₃₋₆cycloalkyl, C₆₋₁₀aryl, 5-6            membered heteroaryl, and 4-6 membered heterocyclyl; wherein            each C₃₋₆cycloalkyl, C₆₋₁₀aryl, 5-6 membered heteroaryl, and            4-6 membered heterocyclyl of R^(b) is independently            optionally substituted with one to three groups            independently selected from halo, cyano, hydroxyl,            —NR^(a1)R^(a2), C₁₋₄alkyl, C₁₋₄ haloalkyl, and C₁₋₄alkoxyl;        -   wherein each R^(b1) and R^(b2) is independently selected            from H, C₁₋₈alkyl, C₁₋₈haloalkyl, C₃₋₈cycloalkyl, C₆₋₁₀aryl,            5-6 membered heteroaryl, and 3-8 membered heterocyclyl;            -   wherein each C₃₋₈cycloalkyl, C₆₋₁₀aryl, 5-6 membered                heteroaryl, and 4-6 membered heterocyclyl of R^(b1) and                R^(b2) is independently optionally substituted with one                to three groups independently selected from halo, cyano,                hydroxyl, —NR^(a1)R^(a2), C₁₋₈alkyl, C₁₋₈haloalkyl,                C₁₋₆alkoxyl, C₃₋₆cycloalkyl, C₆₋₁₀aryl, 5-6 membered                heteroaryl, and 4-6 membered heterocyclyl; and            -   wherein each C₁₋₈alkyl and C₁₋₈haloalkyl of R^(b1) and                R^(b2) is optionally substituted with one to two R^(b5);        -   wherein R^(b3) is C₁₋₄alkylene;        -   wherein R^(b4) is selected from C₁₋₄alkyl, C₁₋₄haloalkyl,            C₃₋₆cycloalkyl, C₆₋₁₀aryl, 5-6 membered heteroaryl, and 4-6            membered heterocyclyl; wherein each C₁₋₄alkyl,            C₁₋₄haloalkyl, C₃₋₈cycloalkyl, C₆₋₁₀aryl, 5-6 membered            heteroaryl, and the 4-6 membered heterocyclyl of R^(b4) is            optionally substituted with one to three R^(b6).        -   wherein each R^(b5) is independently selected from cyano,            hydroxyl, C₁₋₄alkoxyl, C₃₋₈cycloalkyl, C₆₋₁₀aryl, 5-6            membered heteroaryl, and 4-6 membered heterocyclyl; and each            C₁₋₄alkoxyl, C₃₋₈cycloalkyl, C₆₋₁₀aryl, 5-6 membered            heteroaryl, and 4-6 membered heterocyclyl of R^(b5) is            optionally substituted with one to three groups            independently selected from halo, cyano, hydroxyl,            —NR^(a1)R^(a2), C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxyl, and            phenyl; and        -   wherein each R^(b6) is independently selected from halo,            cyano, C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxyl,            C₃₋₆cycloalkyl, phenyl, 4-6 membered heterocyclyl, and 5-6            membered heteroaryl; wherein each C₃₋₆cycloalkyl, 4-6            membered heterocyclyl, and 5-6 membered heteroaryl of R^(b6)            is independently optionally substituted with one to three            groups independently selected from halo, cyano,            —NR^(a1)R^(a2), C₁₋₄alkyl, C₁₋₄haloalkyl, and C₁₋₄alkoxyl;            or    -   R² and R³, R³ and R⁴, or R⁵ and R⁶ together with the atoms to        which they are attached form a C₆₋₁₀aryl, 5-6 membered        heteroaryl, C₃₋₆cycloalkyl, or 5-6 membered heterocyclyl;        wherein each C₆₋₁₀aryl, 5-6 membered heteroaryl, C₃₋₆cycloalkyl,        and 5-6 membered heterocyclyl is independently optionally        substituted with one to three groups independently selected from        halo, cyano, —NR^(a1)R^(a2), C₁₋₆alkyl, C₁₋₆alkoxyl,        C₁₋₆haloalkyl, C₃₋₈cycloalkyl, 3-6 membered heterocyclyl,        C₆₋₁₀aryl, 5-6 membered heteroaryl, C₁₋₄alkylene-C₃₋₈cycloalkyl,        C₁₋₄alkylene-C₆₋₁₀aryl, and C₁₋₄alkylene-(5-6 membered        heteroaryl);

each R⁷, R⁸, R⁹, R¹⁰, R¹¹, and R¹² is independently selected from H,halo, hydroxyl, cyano, C₁₋₆alkyl, C₁₋₆alkoxyl, C₁₋₆haloalkyl,C₁₋₆haloalkoxyl, and —NR^(a1)R^(a2);

R¹³ is selected from H, C₁₋₄alkyl, and C₁₋₄haloalkyl; and

R¹⁴ is selected from H, C₁₋₆alkyl, —C₁₋₄alkylene-NR^(a1)R^(a2),—C₁₋₄alkylene-C(O)NR^(a1)R^(a2), —C₁₋₄alkylene-O—C(O)—C₁₋₄alkyl,—C₁₋₄alkylene-O—C(O)—O—C₁₋₄alkyl,—C₁₋₄alkylene-O—C(O)—C₁₋₄alkylene-NR^(a1)R^(a2),—C₁₋₄alkylene-O—C₁₋₄alkyl, C₃₋₈cycloalkyl, —C₁₋₄alkylene-C₃₋₈cycloalkyl,4-6 membered heterocyclyl, and —C₁₋₄alkylene-(4-6 memberedheterocyclyl);

-   -   wherein each C₃₋₈cycloalkyl, —C₁₋₄alkylene-C₃₋₈cycloalkyl, 4-6        membered heterocyclyl, and —C₁₋₄alkylene-(4-6 membered        heterocyclyl) of R¹⁴ is optionally substituted with one to three        groups independently selected from halo, C₁₋₄alkyl, C₁₋₄        alkoxyl, and C₁₋₄haloalkyl; or    -   R¹⁴ together with the N that attaches to R¹³ forms a 5 membered        heterocyclyl; wherein the 5 membered heterocyclyl is optionally        substituted with one to two groups independently selected from        halo, C₁₋₆alkyl, C₁₋₆alkoxyl, C₁₋₆haloalkyl, and C₆₋₁₀aryl;        wherein the C₆₋₁₀aryl is optionally substituted with one to        three groups independently selected from halo, C₁₋₆alkyl,        C₁₋₆alkoxyl, and C₁₋₆haloalkyl;

each R^(a1) and R^(a2) is independently selected from H, C₁₋₆alkyl, andC₁₋₆haloalkyl;

m is selected from 0, 1, and 2; and

n is selected from 1, and 2.

DETAILED DESCRIPTION Definitions and General Parameters

The following description sets forth exemplary methods, parameters andthe like. It should be recognized, however, that such description is notintended as a limitation on the scope of the present disclosure but isinstead provided as a description of exemplary embodiments.

As used in the present specification, the following words, phrases andsymbols are generally intended to have the meanings as set forth below,except to the extent that the context in which they are used indicatesotherwise.

A dash (“-”) that is not between two letters or symbols is used toindicate a point of attachment for a substituent. For example, —CONH₂ isattached through the carbon atom. A dash at the front or end of achemical group is a matter of convenience; chemical groups may bedepicted with or without one or more dashes without losing theirordinary meaning. A wavy line drawn through a line in a structureindicates a point of attachment of a group. Unless chemically orstructurally required, no directionality is indicated or implied by theorder in which a chemical group is written or named.

A squiggly line on a chemical group as shown below, for example,

indicates a point of attachment, i.e., it shows the broken bond by whichthe group is connected to another described group.

The prefix “C_(u-v)” indicates that the following group has from u to vcarbon atoms. For example, “C₁₋₈ alkyl” indicates that the alkyl grouphas from 1 to 8 carbon atoms.

Reference to “about” a value or parameter herein includes (anddescribes) embodiments that are directed to that value or parameter perse. In certain embodiments, the term “about” includes the indicatedamount ±10%. In other embodiments, the term “about” includes theindicated amount ±5%. In certain other embodiments, the term “about”includes the indicated amount ±1%. Also, to the term “about X” includesdescription of “X”. Also, the singular forms “a” and “the” includeplural references unless the context clearly dictates otherwise. Thus,e.g., reference to “the compound” includes a plurality of such compoundsand reference to “the assay” includes reference to one or more assaysand equivalents thereof known to those skilled in the art.

“Alkyl” refers to an unbranched or branched saturated hydrocarbon chain.As used herein, alkyl has 1 to 20 carbon atoms (i.e., C₁₋₂₀ alkyl), 1 to8 carbon atoms (i.e., C₁₋₈ alkyl), 1 to 6 carbon atoms (i.e., C₁₋₆alkyl), or 1 to 4 carbon atoms (i.e., C₁₋₄ alkyl). Examples of alkylgroups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl,iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl,2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having aspecific number of carbons is named by chemical name or identified bymolecular formula, all positional isomers having that number of carbonsmay be encompassed; thus, for example, “butyl” includes n-butyl (i.e.—(CH₂)₃CH₃), sec-butyl (i.e. —CH(CH₃)CH₂CH₃), isobutyl (i.e.—CH₂CH(CH₃)₂) and tert-butyl (i.e. —C(CH₃)₃); and “propyl” includesn-propyl (i.e. —(CH₂)₂CH₃) and isopropyl (i.e. —CH(CH₃)₂).

“Alkylene” (including those which are part of other groups) refers tobranched and unbranched divalent “alkyl” groups. As used herein,alkylene has 1 to 20 carbon atoms (i.e., C₁₋₂₀alkylene), 1 to 8 carbonatoms (i.e., C₁₋₈ alkylene), 1 to 6 carbon atoms (i.e., C₁₋₆ alkylene),or 1 to 4 carbon atoms (i.e., C₁₋₄ alkylene). Examples include:methylene, ethylene, propylene, 1-methylethylene, butylene,1-methylpropylene, 1,1-dimethylethylene or 1,2-dimethylethylene. Unlessstated otherwise, the definitions propylene and butylene include all thepossible isomeric forms of the groups in question with the same numberof carbons. Thus, for example, propylene also includes 1-methylethyleneand butylene includes 1-methylpropylene, 1,1-dimethylethylene, and1,2-dimethylethylene.

“Alkenyl” refers to an aliphatic group containing at least onecarbon-carbon double bond and having from 2 to 20 carbon atoms (i.e.,C₂₋₂₀ alkenyl), 2 to 8 carbon atoms (i.e., C₂₋₈ alkenyl), 2 to 6 carbonatoms (i.e., C₂₋₆ alkenyl), or 2 to 4 carbon atoms (i.e., C₂₋₄ alkenyl).Examples of alkenyl groups include ethenyl, propenyl, butadienyl(including 1,2-butadienyl and 1,3-butadienyl).

“Alkynyl” refers to an aliphatic group containing at least onecarbon-carbon triple bond and having from 2 to 20 carbon atoms (i.e.,C₂₋₂₀ alkynyl), 2 to 8 carbon atoms (i.e., C₂₋₈ alkynyl), 2 to 6 carbonatoms (i.e., C₂₋₆ alkynyl), or 2 to 4 carbon atoms (i.e., C₂₋₄ alkynyl).The term “alkynyl” also includes those groups having one triple bond andone double bond.

“Alkoxy” and “alkoxyl” are used interchangeably and refer to the group“alkyl-O—”. Examples of alkoxyl and alkoxy groups include methoxy,ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy,n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. “Haloalkoxyl” refers to analkoxyl group as defined above, wherein one or more hydrogen atoms arereplaced by a halogen.

“Acyl” refers to a group —C(═O)R, wherein R is hydrogen, alkyl,cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each ofwhich may be optionally substituted, as defined herein. Examples of acylinclude formyl, acetyl, cylcohexylcarbonyl, cyclohexylmethyl-carbonyl,and benzoyl.

“Aryl” refers to an aromatic carbocyclic group having a single ring(e.g. monocyclic) or multiple rings (e.g. bicyclic or tricyclic)including fused systems. As used herein, aryl has 6 to 20 ring carbonatoms (i.e., C₆₋₂₀ aryl), 6 to 12 carbon ring atoms (i.e., C₆₋₁₂ aryl),or 6 to 10 carbon ring atoms (i.e., C₆₋₁₀ aryl). Examples of aryl groupsinclude phenyl, naphthyl, fluorenyl, and anthryl. Aryl, however, doesnot encompass or overlap in any way with heteroaryl defined below. Ifone or more aryl groups are fused with a heteroaryl ring, the resultingring system is heteroaryl.

“Azido” refers to the group —N₃.

“Cyano” or “carbonitrile” refers to the group —CN.

“Cycloalkyl” refers to a saturated or partially saturated cyclic alkylgroup having a single ring or multiple rings including fused, bridged,and spiro ring systems. The term “cycloalkyl” includes cycloalkenylgroups (i.e. the cyclic group having at least one double bond). As usedherein, cycloalkyl has from 3 to 20 ring carbon atoms (i.e., C₃₋₂₀cycloalkyl), 3 to 12 ring carbon atoms (i.e., C₃₋₁₂ cycloalkyl), 3 to 10ring carbon atoms (i.e., C₃₋₁₀ cycloalkyl), 3 to 8 ring carbon atoms(i.e., C₃₋₈ cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C₃₋₆cycloalkyl). Examples of cycloalkyl groups include cyclopropyl,cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyl groups also includepartially unsaturated ring systems containing one or more double bonds,including fused ring systems with one aromatic ring and one non-aromaticring, but not fully aromatic ring systems.

“Bridged” refers to a ring fusion wherein non-adjacent atoms on a ringare joined by a divalent substituent, such as an alkylenyl orheteroalkylenyl group or a single heteroatom. Quinuclidinyl andadamantanyl are examples of bridged ring systems.

The term “fused” refers to a ring which is bound to an adjacent ring.

“Spiro” refers to a ring substituent which is joined by two bonds at thesame carbon atom. Examples of spiro groups include1,1-diethylcyclopentane, dimethyl-dioxolane, and4-benzyl-4-methylpiperidine, wherein the cyclopentane and piperidine,respectively, are the spiro substituents.

“Spiro” also refers to a bicyclic portion, wherein the two rings areconnected through a single common atom. Spiro compounds may be fullycarbocyclic or heterocyclic. Examples of spiro groups include5-oxa-8-azaspiro[3.5]nonane, 7-oxa-4-azaspiro[2.5]octane, and5λ²-azaspiro[2.4]heptane.

“Halogen” or “halo” includes fluoro, chloro, bromo, and iodo.“Haloalkyl” refers to an unbranched or branched alkyl group as definedabove, wherein one or more hydrogen atoms are replaced by a halogen. Forexample, where a residue is substituted with more than one halogen, itmay be referred to by using a prefix corresponding to the number ofhalogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkylsubstituted with two (“di”) or three (“tri”) halo groups, which may be,but are not necessarily, the same halogen. Examples of haloalkyl includedifluoromethyl (—CHF₂) and trifluoromethyl (—CF₃).

The term “heterocyclyl” or “heterocycle” as used herein refers to asingle saturated or partially unsaturated non-aromatic ring or anon-aromatic multiple ring system that has at least one heteroatom inthe ring (i.e., at least one annular heteroatom selected from O, N, S,S(O), S(O)₂, and N-oxide groups). Unless otherwise specified, aheterocyclyl group has from 3 to about 20 annular atoms, for examplefrom 3 to 12 annular atoms, for example from 3 to 10 annular atoms, forexample from 5 to 10 annular atoms or for example from 5 to 6 annularatoms. Thus, the term includes single saturated or partially unsaturatedrings (e.g., 3, 4, 5, 6 or 7-membered rings) having from about 1 to 6annular carbon atoms and from about 1 to 3 annular heteroatomsindependently selected from the group consisting of O, N, S, S(O),S(O)₂, and N-oxide in the ring. The rings of the multiple condensed ring(e.g. bicyclic heterocyclyl) system can be connected to each other viafused, spiro and bridged bonds when allowed by valency requirements.Heterocycles include, but are not limited to, groups derived fromazetidine, aziridine, imidazolidine, morpholine, oxirane (epoxide),oxetane, piperazine, piperidine, pyrazolidine, piperidine, pyrrolidine,pyrrolidinone, tetrahydrofuran, tetrahydrothiophene, dihydropyridine,tetrahydropyridine, tetrahydro-2H-thiopyran 1,1-dioxide, quinuclidine,N-bromopyrrolidine, N-chloropiperidine, and the like. Heterocyclesinclude spirocycles, such as, for example, aza or oxo-spiroheptanes.Heterocyclyl groups also include partially unsaturated ring systemscontaining one or more double bonds, including fused ring systems withone aromatic ring and one non-aromatic ring, but not fully aromatic ringsystems. Examples include dihydroquinolines, e.g. 3,4-dihydroquinoline,dihydroisoquinolines, e.g. 1,2-dihydroisoquinoline, dihydroimidazole,tetrahydroimidazole, etc., indoline, isoindoline, isoindolones (e.g.isoindolin-1-one), isatin, dihydrophthalazine, quinolinone,spiro[cyclopropane-1,1′-isoindolin]-3′-one, and the like. Additionalexamples of heterocycles include 3,8-diazabicyclo[3.2.1]octanyl,2,5-diazabicyclo [2.2.1]heptanyl, 3,6-diazabicyclo[3.1.1]heptanyl,3-oxa-7,9-diazabicyclo[3.3.1]nonanyl, andhexahydropyrazino[2,1-c][1,4]oxazinyl, for example.

“Hydroxyl” and “hydroxy” are used interchangeably and refer to —OH.“Oxo” refers to the group (═O) or (O). Where tautomeric forms of thecompound exist, hydroxyl and oxo groups are interchangeable.

“Heteroaryl” refers to an aromatic group, including groups having anaromatic tautomer or resonance structure, having a single ring, multiplerings, or multiple fused rings, with at least one heteroatom in thering, i.e., one or more ring heteroatoms independently selected fromnitrogen, oxygen, and sulfur, wherein the nitrogen or sulfur may beoxidized. Thus, the term includes rings having one or more annular O, N,S, S(O), S(O)₂, and N-oxide groups. The term includes rings having oneor more annular C(O) groups. As used herein, heteroaryl include 5 to 20ring atoms (i.e., 5- to 20-membered heteroaryl), 5 to 12 ring atoms(i.e., 5- to 12-membered heteroaryl), or 5 to 10 ring atoms (i.e., 5- to10-membered heteroaryl), and 1 to 5 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur, and oxidized forms of theheteroatoms. Examples of heteroaryl groups include pyridin-2(1H)-one,pyridazin-3(2H)-one, pyrimidin-4(3H)-one, quinolin-2(1H)-one,pyrimidinyl, purinyl, pyridyl, pyridazinyl, benzothiazolyl, andpyrazolyl. Heteroaryl does not encompass or overlap with aryl as definedabove.

“Sulfonyl” refers to the group —S(O)₂R, where R is alkyl, haloalkyl,heterocyclyl, cycloalkyl, heteroaryl, or aryl. Examples of sulfonyl aremethylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.

Whenever the graphical representation of a group terminates in a singlybonded nitrogen atom, that group represents an —NH group unlessotherwise indicated. Similarly, unless otherwise expressed, hydrogenatom(s) are implied and deemed present where necessary in view of theknowledge of one of skill in the art to complete valency or providestability.

Certain commonly used alternative chemical names may be used. Forexample, a divalent group such as a divalent “alkyl” group, a divalent“aryl” group, etc., may also be referred to as an “alkylene” group or an“alkylenyl” group, an “arylene” group or an “arylenyl” group,respectively. Also, unless indicated explicitly otherwise, wherecombinations of groups are referred to herein as one moiety, e.g.arylalkyl, the last mentioned group contains the atom by which themoiety is attached to the rest of the molecule.

The terms “optional” or “optionally” means that the subsequentlydescribed event or circumstance may or may not occur, and that thedescription includes instances where said event or circumstance occursand instances in which it does not. Also, the term “optionallysubstituted” refers to any one or more hydrogen atoms on the designatedatom or group may or may not be replaced by a moiety other thanhydrogen.

The term “substituted” means that any one or more hydrogen atoms on thedesignated atom or group is replaced with one or more substituents otherthan hydrogen, provided that the designated atom's normal valence is notexceeded. The one or more substituents include, but are not limited to,alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl,azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo,haloalkyl, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino,imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl,thiocyanate, thiol, thione, or combinations thereof. Polymers or similarindefinite structures arrived at by defining substituents with furthersubstituents appended ad infinitum (e.g., a substituted aryl having asubstituted alkyl which is itself substituted with a substituted arylgroup, which is further substituted by a substituted heteroalkyl group,etc.) are not intended for inclusion herein. Unless otherwise noted, themaximum number of serial substitutions in compounds described herein isthree. For example, serial substitutions of substituted aryl groups withtwo other substituted aryl groups are limited to ((substitutedaryl)substituted aryl) substituted aryl. Similarly, the abovedefinitions are not intended to include impermissible substitutionpatterns (e.g., methyl substituted with 5 fluorines or heteroaryl groupshaving two adjacent oxygen ring atoms). Such impermissible substitutionpatterns are well known to the skilled artisan. When used to modify achemical group, the term “substituted” may describe other chemicalgroups defined herein. For example, the term “substituted aryl”includes, but is not limited to, “alkylaryl.” Unless specifiedotherwise, where a group is described as optionally substituted, anysubstituents of the group are themselves unsubstituted.

In some embodiments, the term “substituted alkyl” refers to an alkylgroup having one or more substituents including hydroxyl, halo, alkoxy,cycloalkyl, heterocyclyl, aryl, and heteroaryl. In additionalembodiments, “substituted cycloalkyl” refers to a cycloalkyl grouphaving one or more substituents including alkyl, haloalkyl, cycloalkyl,heterocyclyl, aryl, heteroaryl, alkoxy, halo, oxo, and hydroxyl;“substituted heterocyclyl” refers to a heterocyclyl group having one ormore substituents including alkyl, haloalkyl, heterocyclyl, cycloalkyl,aryl, heteroaryl, alkoxy, halo, oxo, and hydroxyl; “substituted aryl”refers to an aryl group having one or more substituents including halo,alkyl, haloalkyl, cycloalkyl, heterocyclyl, heteroaryl, alkoxy, andcyano; “substituted heteroaryl” refers to an heteroaryl group having oneor more substituents including halo, alkyl, haloalkyl, heterocyclyl,heteroaryl, alkoxy, and cyano and “substituted sulfonyl” refers to agroup —S(O)₂R, in which R is substituted with one or more substituentsincluding alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl. Inother embodiments, the one or more substituents may be furthersubstituted with halo, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl,heterocyclyl, aryl, or heteroaryl, each of which is substituted. Inother embodiments, the substituents may be further substituted withhalo, alkyl, haloalkyl, alkoxy, hydroxyl, cycloalkyl, heterocyclyl,aryl, or heteroaryl, each of which is unsubstituted.

Some of the compounds exist as tautomeric isomers. Tautomeric isomersare in equilibrium with one another. For example, amide containingcompounds may exist in equilibrium with imidic acid tautomers.Regardless of which tautomer is shown, and regardless of the nature ofthe equilibrium among tautomers, the compounds are understood by one ofordinary skill in the art to comprise both amide and imidic acidtautomers. Thus, the amide containing compounds are understood toinclude their imidic acid tautomers. Likewise, the imidic acidcontaining compounds are understood to include their amide tautomers.

Any formula or structure given herein, is also intended to representunlabeled forms as well as isotopically labeled forms of the compounds.Isotopically labeled compounds have structures depicted by the formulasgiven herein except that one or more atoms are replaced by an atomhaving a selected atomic mass or mass number. Examples of isotopes thatcan be incorporated into compounds of the disclosure include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine,such as, but not limited to ²H (deuterium, D), ³H (tritium), ¹¹C, ¹³C,¹⁴C, ¹⁵N, ¹⁸F, ³¹P, ³²P, ³⁵S, ³⁶Cl and ¹²⁵I. Various isotopicallylabeled compounds of the present disclosure, for example those intowhich radioactive isotopes such as ³H, ¹³C and ¹⁴C are incorporated.Such isotopically labelled compounds may be useful in metabolic studies,reaction kinetic studies, detection or imaging techniques, such aspositron emission tomography (PET) or single-photon emission computedtomography (SPECT) including drug or substrate tissue distributionassays or in radioactive treatment of patients.

The disclosure also includes compounds of the present disclosure, inwhich from 1 to n hydrogens attached to a carbon atom is/are replaced bydeuterium, in which n is the number of hydrogens in the molecule. Suchcompounds exhibit increased resistance to metabolism and are thus usefulfor increasing the half-life of any compound of the present disclosure,when administered to a mammal, particularly a human. See, for example,Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,”Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds aresynthesized by means well known in the art, for example by employingstarting materials in which one or more hydrogens have been replaced bydeuterium.

Deuterium labelled or substituted therapeutic compounds of thedisclosure may have improved DMPK (drug metabolism and pharmacokinetics)properties, relating to distribution, metabolism and excretion (ADME).Substitution with heavier isotopes such as deuterium may afford certaintherapeutic advantages resulting from greater metabolic stability, forexample increased in vivo half-life, reduced dosage requirements and/oran improvement in therapeutic index. An ¹⁸F labeled compound may beuseful for PET or SPECT studies. Isotopically labeled compounds of thisdisclosure and prodrugs thereof can generally be prepared by carryingout the procedures disclosed in the schemes or in the examples andpreparations described below by substituting a readily availableisotopically labeled reagent for a non-isotopically labeled reagent. Itis understood that deuterium in this context is regarded as asubstituent in the compound of the present disclosure.

The concentration of such a heavier isotope, specifically deuterium, maybe defined by an isotopic enrichment factor. In the compounds of thisdisclosure any atom not specifically designated as a particular isotopeis meant to represent any stable isotope of that atom. Unless otherwisestated, when a position is designated specifically as “H” or “hydrogen”,the position is understood to have hydrogen at its natural abundanceisotopic composition. Accordingly, in the compounds of this disclosureany atom specifically designated as a deuterium (D) is meant torepresent deuterium.

In many cases, the compounds of this disclosure are capable of formingacid and/or base salts by virtue of the presence of amino and/orcarboxyl groups or groups similar thereto.

The term “pharmaceutically acceptable salt” of a given compound refersto salts that retain the biological effectiveness and properties of thegiven compound, and which are not biologically or otherwise undesirable.Pharmaceutically acceptable base addition salts can be prepared frominorganic and organic bases. Salts derived from inorganic bases include,by way of example only, sodium, potassium, lithium, ammonium, calciumand magnesium salts. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary and tertiary amines, such asalkyl amines, dialkyl amines, trialkyl amines, substituted alkyl amines,di(substituted alkyl) amines, tri(substituted alkyl) amines, alkenylamines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines,di(substituted alkenyl) amines, tri(substituted alkenyl) amines, mono,di or tri cycloalkyl amines, mono, di or tri arylamines or mixed amines,etc. Specific examples of suitable amines include, by way of exampleonly, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl)amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol,piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

Pharmaceutically acceptable acid addition salts may be prepared frominorganic and organic acids. Salts derived from inorganic acids includehydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like. Salts derived from organic acids includeacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid,malic acid, malonic acid, succinic acid, maleic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid,salicylic acid, and the like.

Salts, such as TFA salts, can be converted to the free-bases/acids orother pharmaceutically acceptable salts.

As used herein, “pharmaceutically acceptable carrier” or“pharmaceutically acceptable excipient” includes any and all solvents,dispersion media, coatings, antibacterial and antifungal agents,isotonic and absorption delaying agents and the like. The use of suchmedia and agents for pharmaceutically active substances is well known inthe art. Except insofar as any conventional media or agent isincompatible with the active ingredient, its use in the therapeuticcompositions is contemplated. Supplementary active ingredients can alsobe incorporated into the compositions.

“Treatment” or “treating” is an approach for obtaining beneficial ordesired results including clinical results. Beneficial or desiredclinical results may include one or more of the following: a) inhibitingthe disease or condition (e.g., decreasing one or more symptomsresulting from the disease or condition, and/or diminishing the extentof the disease or condition); b) slowing or arresting the development ofone or more clinical symptoms associated with the disease or condition(e.g., stabilizing the disease or condition, preventing or delaying theworsening or progression of the disease or condition, and/or preventingor delaying the spread (e.g., metastasis) of the disease or condition);and/or c) relieving the disease, that is, causing the regression ofclinical symptoms (e.g., ameliorating the disease state, providingpartial or total remission of the disease or condition, enhancing effectof another medication, delaying the progression of the disease,increasing the quality of life, and/or prolonging survival.

“Prevention” or “preventing” means any treatment of a disease orcondition that causes the clinical symptoms of the disease or conditionnot to develop. Compounds may, in some embodiments, be administered to asubject (including a human) who is at risk or has a family history ofthe disease or condition.

“Subject” refers to an animal, such as a mammal (including a human),that has been or will be the object of treatment, observation orexperiment. The methods described herein may be useful in human therapyand/or veterinary applications. In some embodiments, the subject is amammal. In one embodiment, the subject is a human.

The term “therapeutically effective amount” or “effective amount” of acompound described herein or pharmaceutically acceptable salts, isomer,or a mixture thereof means an amount sufficient to effect treatment whenadministered to a subject, to provide a therapeutic benefit such asamelioration of symptoms or slowing of disease progression. For example,a therapeutically effective amount may be an amount sufficient todecrease a symptom of a disease or condition responsive to inhibition ofα4β7 integrin activity. The therapeutically effective amount may varydepending on the subject, and disease or condition being treated, theweight and age of the subject, the severity of the disease or condition,and the manner of administering, which can readily be determined by oneor ordinary skill in the art.

The term “inhibition” indicates a decrease in the baseline activity of abiological activity or process. “Inhibition of activity of α4β7integrin” or variants thereof refers to a decrease in activity of α4β7integrin as a direct or indirect response to the presence of a compoundof the present application relative to the activity of α4β7 integrin inthe absence of the compound of the present application. “Inhibition ofα4β7” refers to a decrease in α4β7 integrin activity as a direct orindirect response to the presence of a compound described hereinrelative to the activity of α4β7 integrin in the absence of the compounddescribed herein. In some embodiments, the inhibition of α4β7 integrinactivity may be compared in the same subject prior to treatment, orother subjects not receiving the treatment.

Compounds

Provided herein are compounds that function as inhibitors of α4β7integrin. In one aspect, provided is a compound having structure ofFormula (I), or a pharmaceutically acceptable salt thereof:

R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, and L aredefined as above.

In another aspect, provided are compounds of Formula (II), orpharmaceutically acceptable salts thereof:

L is selected from a bond, —O—, —O—C(O)—*, —NH—, —C(O)—N(H)—*, and—N(H)—C(O)—*; wherein * indicates the point of attachment of L to R¹;

R¹ is selected from A¹, A², and A³;

-   -   A¹ is 5-10 membered heteroaryl containing one to five        heteroatoms independently selected from S, N, and O; wherein A¹        optionally comprises one to three C(O); and wherein A¹ is        optionally substituted with one to six R^(a);    -   A² is C₆₋₁₀aryl, optionally substituted with one to six R^(a);        and    -   A³ is C₅₋₁₀cycloalkyl or 5-14 membered heterocyclyl; wherein A³        is optionally substituted with one to four groups independently        selected from oxo and R^(a); and    -   wherein each R^(a) is independently selected from halo, cyano,        hydroxyl, —NR^(a1)R^(a2), C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,        C₁₋₆alkoxyl, C₁₋₆haloalkyl, C₁₋₆haloalkoxyl,        —S(O)_(m)—C₁₋₆alkyl, C₃₋₈cycloalkyl, 3-6 membered heterocyclyl,        C₆₋₁₀aryl, 5-6 membered heteroaryl, —O—C₃₋₈cycloalkyl, —O-(3-6        membered heterocyclyl), —O—C₁₋₄alkylene-C₃₋₈cycloalkyl, and        —O-phenyl;        -   wherein each C₃₋₈cycloalkyl, 3-6 membered heterocyclyl,            C₆₋₁₀aryl, 5-6 membered heteroaryl, —O—C₃₋₈cycloalkyl,            —O-(3-6 membered heterocyclyl),            —O—C₁₋₄alkylene-C₃₋₈cycloalkyl, and —O-phenyl of R^(a) is            independently optionally substituted with one to three            groups independently selected from halo, cyano, hydroxyl,            —NR^(a1)R^(a2), C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxyl, and            C₁₋₆haloalkoxyl; and        -   wherein each C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,            C₁₋₆alkoxyl, C₁₋₆haloalkyl, C₁₋₆haloalkoxyl, and            —S(O)_(m)—C₁₋₆alkyl of R^(a) is optionally substituted with            one to three R^(a3), wherein each R^(a3) is independently            selected from halo, cyano, hydroxyl, —NR^(a1)R^(a2),            C₁₋₆alkoxyl, C₃₋₈cycloalkyl, and 3-6 membered heterocyclyl;        -   wherein each C₃₋₈cycloalkyl and 3-6 membered heterocyclyl of            R^(a3) is optionally substituted with one to three R^(a4);            and each R^(a4) is independently selected from halo, cyano,            hydroxyl, —NR^(a1)R^(a2), C₁₋₆alkyl, C₁₋₆haloalkyl,            C₁₋₆alkoxyl, C₁₋₆haloalkoxyl, C₃₋₈cycloalkyl, and 3-6            membered heterocyclyl;

each R², R³, R⁴, R⁵, and R⁶ is independently selected from H, halo,cyano, hydroxyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxyl,C₁₋₈haloalkyl, C₁₋₈haloalkoxyl, —NR^(b1)R^(b2), —R^(b3)S(O)_(m)R^(b4),—S(O)_(m)R^(b4), —NR^(b1)S(O)_(n)R^(b4), —COOR^(b1), —CONR^(b1)R^(b2),—NR^(b1)COOR^(b2), —NR^(b1)COR^(b4), —R^(b3)NR^(b1)R^(b2),—S(O)_(n)NR^(b1)R^(b2), C₃₋₁₂cycloalkyl, C₆₋₁₀aryl, 5-6 memberedheteroaryl, and 3-12 membered heterocyclyl;

-   -   wherein each C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxyl,        C₁₋₆haloalkyl, and C₁₋₆haloalkoxyl of R², R³, R⁴, R⁵, and R⁶ is        optionally substituted with one to two R^(c); wherein each R^(c)        is independently selected from azido, oxo, cyano, halo,        hydroxyl, —NR^(a1)R^(a2), C₁₋₄alkoxyl, C₃₋₈cycloalkyl,        C₆₋₁₀aryl, 5-6 membered heteroaryl, and 4-6 membered        heterocyclyl; wherein each C₃₋₈cycloalkyl, C₆₋₁₀aryl, 5-6        membered heteroaryl, and 4-6 membered heterocyclyl of R^(c) is        optionally substituted with one to three groups independently        selected from halo, cyano, hydroxyl, —NR^(a1)R^(a2), C₁₋₄alkyl,        C₁₋₆haloalkyl, C₁₋₄alkoxyl, and C₃₋₆cycloalkyl;    -   wherein each C₆₋₁₀aryl, and 5-6 membered heteroaryl of R², R³,        R⁴, R⁵, and R⁶ is independently optionally substituted with one        to five R^(b); and    -   wherein each C₃₋₁₂cycloalkyl, and 3-12 membered heterocyclyl of        R², R³, R⁴, R⁵, and R⁶ is independently optionally substituted        with one to six groups independently selected from        ═CR^(b1)R^(b2) and R^(b);        -   wherein each R^(b) is independently selected from azido,            cyano, halo, hydroxyl, —NR^(a1)R^(a2), C₁₋₆alkyl,            C₁₋₈haloalkyl, C₁₋₆alkoxyl, C₃₋₆cycloalkyl, C₆₋₁₀aryl, 5-6            membered heteroaryl, and 4-6 membered heterocyclyl; wherein            each C₃₋₆cycloalkyl, C₆₋₁₀aryl, 5-6 membered heteroaryl, and            4-6 membered heterocyclyl of R^(b) is independently            optionally substituted with one to three groups            independently selected from halo, cyano, hydroxyl,            —NR^(a1)R^(a2), C₁₋₄alkyl, C₁₋₄ haloalkyl, and C₁₋₄alkoxyl;        -   wherein each R^(b1) and R^(b2) is independently selected            from H, C₁₋₈alkyl, C₁₋₈haloalkyl, C₃₋₈cycloalkyl, C₆₋₁₀aryl,            5-6 membered heteroaryl, and 3-8 membered heterocyclyl;            -   wherein each C₃₋₈cycloalkyl, C₆₋₁₀aryl, 5-6 membered                heteroaryl, and 4-6 membered heterocyclyl of R^(b1) and                R^(b2) is independently optionally substituted with one                to three groups independently selected from halo, cyano,                hydroxyl, —NR^(a1)R^(a2), C₁₋₈alkyl, C₁₋₈haloalkyl,                C₁₋₆alkoxyl, C₃₋₆cycloalkyl, C₆₋₁₀aryl, 5-6 membered                heteroaryl, and 4-6 membered heterocyclyl; and            -   wherein each C₁₋₈alkyl and C₁₋₈haloalkyl of R^(b1) and                R^(b2) is optionally substituted with one to two R^(b5);        -   wherein R^(b3) is C₁₋₄alkylene;        -   wherein R^(b4) is selected from C₁₋₄alkyl, C₁₋₄haloalkyl,            C₃₋₆cycloalkyl, C₆₋₁₀aryl, 5-6 membered heteroaryl, and 4-6            membered heterocyclyl; wherein each C₁₋₄alkyl,            C₁₋₄haloalkyl, C₃₋₈cycloalkyl, C₆₋₁₀aryl, 5-6 membered            heteroaryl, and the 4-6 membered heterocyclyl of R^(b4) is            optionally substituted with one to three R^(b6).        -   wherein each R^(b5) is independently selected from cyano,            hydroxyl, C₁₋₄alkoxyl, C₃₋₈cycloalkyl, C₆₋₁₀aryl, 5-6            membered heteroaryl, and 4-6 membered heterocyclyl; and each            C₁₋₄alkoxyl, C₃₋₈cycloalkyl, C₆₋₁₀aryl, 5-6 membered            heteroaryl, and 4-6 membered heterocyclyl of R^(b5) is            optionally substituted with one to three groups            independently selected from halo, cyano, hydroxyl,            —NR^(a1)R^(a2), C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxyl, and            phenyl; and        -   wherein each R^(b6) is independently selected from halo,            cyano, C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxyl,            C₃₋₆cycloalkyl, phenyl, 4-6 membered heterocyclyl, and 5-6            membered heteroaryl; wherein each C₃₋₆cycloalkyl, 4-6            membered heterocyclyl, and 5-6 membered heteroaryl of R^(b6)            is independently optionally substituted with one to three            groups independently selected from halo, cyano,            —NR^(a1)R^(a2), C₁₋₄alkyl, C₁₋₄haloalkyl, and C₁₋₄alkoxyl;            or    -   R² and R³, R³ and R⁴, or R⁵ and R⁶ together with the atoms to        which they are attached form a C₆₋₁₀aryl, 5-6 membered        heteroaryl, C₃₋₆cycloalkyl, or 5-6 membered heterocyclyl;        wherein each C₆₋₁₀aryl, 5-6 membered heteroaryl, C₃₋₆cycloalkyl,        and 5-6 membered heterocyclyl is independently optionally        substituted with one to three groups independently selected from        halo, cyano, —NR^(a1)R^(a2), C₁₋₆alkyl, C₁₋₆alkoxyl,        C₁₋₆haloalkyl, C₃₋₈cycloalkyl, 3-6 membered heterocyclyl,        C₆₋₁₀aryl, 5-6 membered heteroaryl, C₁₋₄alkylene-C₃₋₈cycloalkyl,        C₁₋₄alkylene-C₆₋₁₀aryl, and C₁₋₄alkylene-(5-6 membered        heteroaryl);

each R⁷, R⁸, R⁹, R¹⁰, and R¹¹ is independently selected from H, halo,hydroxyl, cyano, C₁₋₆alkyl, C₁₋₆alkoxyl, C₁₋₆haloalkyl, C₁₋₆haloalkoxyl,and —NR^(a1)R^(a2);

R¹³ is selected from H, C₁₋₄alkyl, and C₁₋₄haloalkyl; and

R¹⁴ is selected from H, C₁₋₆alkyl, —C₁₋₄alkylene-NR^(a1)R^(a2),—C₁₋₄alkylene-C(O)NR^(a1)R^(a2), —C₁₋₄alkylene-O—C(O)—C₁₋₄alkyl,—C₁₋₄alkylene-O—C(O)—O—C₁₋₄alkyl,—C₁₋₄alkylene-O—C(O)—C₁₋₄alkylene-NR^(a1)R^(a2),—C₁₋₄alkylene-O—C₁₋₄alkyl, C₃₋₈cycloalkyl, —C₁₋₄alkylene-C₃₋₈cycloalkyl,4-6 membered heterocyclyl, and —C₁₋₄alkylene-(4-6 memberedheterocyclyl);

-   -   wherein C₃₋₈cycloalkyl, —C₁₋₄alkylene-C₃₋₈cycloalkyl, 4-6        membered heterocyclyl, and —C₁₋₄alkylene-(4-6 membered        heterocyclyl) of R¹⁴ is optionally substituted with one to three        groups independently selected from halo, C₁₋₄alkyl, C₁₋₄alkoxyl,        and C₁₋₄haloalkyl; or    -   R¹⁴ together with the N that attaches to R¹³ forms a 5 membered        heterocyclyl; wherein the 5 membered heterocyclyl is optionally        substituted with one to two groups independently selected from        halo, C₁₋₆alkyl, C₁₋₆alkoxyl, C₁₋₆haloalkyl, and C₆₋₁₀aryl;        wherein the C₆₋₁₀aryl is optionally substituted with one to        three groups independently selected from halo, C₁₋₆alkyl,        C₁₋₆alkoxyl, and C₁₋₆haloalkyl;

each R^(a1) and R^(a2) is independently selected from H, C₁₋₆alkyl, andC₁₋₆haloalkyl;

m is selected from 0, 1, and 2; and

n is selected from 1, and 2.

In another aspect, provided are compounds of Formula (IIa), orpharmaceutically acceptable salts thereof:

wherein R¹, R², R³, R⁵, R⁶, R¹⁴, R^(b)1, and R^(b2) are as defined abovein formula (I), (II), or elsewhere in this disclosure.

In another aspect, provided are compounds of Formula (IIb), orpharmaceutically acceptable salts thereof:

wherein R¹, R², R³, R⁵, R⁶, R¹⁴, and R^(b) are as defined above informula (I), (II), or elsewhere in this disclosure. X¹ is selected fromCR^(x1), and N; and X² is selected from CR^(x1)R^(x2), NR^(x2), O, andS(O)₂. R^(x1) is selected from H, and R^(b); and R^(x2) is selected fromH, C₁₋₄alkyl, and C₁₋₄haloalkyl. p is selected from 0, 1, and 2. q isselected from 0, 1, 2, 3, and 4.

In another aspect, provided are compounds of Formula (IIc), orpharmaceutically acceptable salts thereof:

wherein R¹, R², R³, R⁵, R⁶, R¹⁴, and R^(b4) are as defined above informula (I), (II), or elsewhere in this disclosure.

In another aspect, provided are compounds of Formula (IId), orpharmaceutically acceptable salts thereof:

Each Y¹, Y², Y³, Y⁴, and Y⁵ is independently selected from CR^(y), andN. R^(y) is selected from H, and R^(a). R^(a), R², R³, R⁴, R⁵, R⁶, andR¹⁴ are as defined above in formula (I), (II), or elsewhere in thisdisclosure.

In another aspect, provided are compounds of Formula (IIe), orpharmaceutically acceptable salts thereof:

wherein R^(a), R², R⁴, R⁶, and R¹⁴ are as defined above in formula (I),(II), or elsewhere in this disclosure. u is selected from 0, 1, 2, 3, 4,and 5.

In another aspect, provided are compounds of Formula (IIf), orpharmaceutically acceptable salts thereof:

wherein R^(y) is independently selected from H, and R^(a). R^(a), R²,R⁴, R⁶, and R¹⁴ are as defined above in formula (I), (II), or elsewherein this disclosure.

In another aspect, provided are compounds of Formula (IIg), orpharmaceutically acceptable salts thereof:

wherein R^(a), R², R³, R⁴, R⁵, R⁶, and R¹⁴ are as defined above informula (I), (II), or elsewhere in this disclosure. Y³, Y⁴, and Y⁵ areas defined above in formula (IId), or elsewhere in this disclosure. EachR^(y) is independently selected from H, and R^(a).

In another aspect, provided are compounds of Formula (IIh), orpharmaceutically acceptable salts thereof:

wherein R², R³, R⁴, R⁵, R⁶, and R¹⁴ are as defined above in formula (I),(II), or elsewhere in this disclosure. Each R^(y) is independently asdefined above in formula (IId), or elsewhere in this disclosure.

In another aspect, provided are compounds of Formula (IIi), orpharmaceutically acceptable salts thereof:

wherein R^(a), R², R³, R⁴, R⁵, R⁶, and R¹⁴ are as defined above informula (I), (II), or elsewhere in this disclosure. r is selected from0, 1, 2, 3, 4, 5, and 6.

In some embodiments of formula (I), or (II), L is a bond. In someembodiments, L is —O—. In some embodiments, L is —C(O)—N(H)—*.

In some embodiments of formula (I), (II), (IIa), (IIb), or (IIc), R¹ isselected from phenyl, naphthyl, pyridinyl, pyridazinyl, pyrazinyl,pyrimidinyl, quinolinyl, isoquinolinyl, isoxazolyl, triazolyl,pyrazolyl, benzothiazolyl, pyridinonyl, quinolinonyl, isoquinolinonyl,quinazolinedionyl, pyrazinonyl, pyrimidinonyl, pyrimidinedionyl,pyridazinonyl, quinazolinonyl, benzofuranyl,tetrahydrocyclopenta[b]pyridinonyl, naphthyridinonyl, chromanyl,isochromanyl, and chromenonyl. Each R¹ is independently optionallysubstituted with one to four R^(a). In some embodiments, R¹ is selectedfrom phenyl, naphthyl, pyridinyl, pyrimidinyl, quinolinyl, isoxazolyl,pyridinonyl, quinolinonyl, quinazolinedionyl, pyrazinonyl,pyrimidinonyl, pyridazinonyl, quinazolinonyl, benzofuranyl, andchromenonyl, and each R¹ is independently optionally substituted withone to four R^(a).

In some embodiments of formula (I), or (II), “R¹-L-” is selected from

and N Each “R¹-L-” is optionally substituted with one to four R^(a). Insome embodiments, each R^(a) is independently selected from halo, cyano,hydroxyl, NR^(a1)R^(a2), C₁₋₄alkyl, C₁₋₄alkoxyl, C₁₋₄haloalkyl,C₁₋₄haloalkoxyl, C₃₋₆cycloalkyl, —O—C₃₋₆cycloalkyl, 3-6 memberedheterocyclyl, —O-(3-6 membered heterocyclyl), and phenyl. In someembodiments, each R^(a) is independently selected from F, Cl, ON, OH,—NH₂, —OH₃, —CH₂F, —CHF₂, —OF₃, —OCH₃, and —OCF₃.

In some embodiments of formula (I), or (II), “R¹-L-” is selected from

Each “R¹-L-” is optionally substituted with one to four R^(a). In someembodiments, each R^(a) is independently selected from halo, cyano,hydroxyl, NR^(a1)R^(a2), C₁₋₄alkyl, C₁₋₄alkoxyl, C₁₋₄haloalkyl,C₁₋₄haloalkoxyl, C₃₋₆cycloalkyl, —O—C₃₋₆cycloalkyl, and phenyl. In someembodiments, each R^(a) is independently selected from F, Cl, CN, OH,—NH₂, —CH₃, —CH₂F, —CHF₂, —CF₃, —OCH₃, and —OCF₃.

In some embodiments of formula (I), (II), (IIa), (IIb), or (IIc), R¹ isselected from

Each R¹ is optionally substituted with one to four R^(a).

In some embodiments of formula (I), (II), (IIa), (IIb), or (IIc), R¹ isselected from

Each R¹ is optionally substituted with one to four R^(a).

In some embodiments of formula (I), (II), (IIa), (IIb), or (IIc), R¹ isselected from

each R¹ is optionally substituted with one to four R^(a). In someembodiments, each R^(a) is independently selected from halo, CN, —OH,NR^(a1)R^(a2), C₁₋₄alkyl, C₁₋₄alkoxyl, C₁₋₄haloalkyl, C₁₋₄haloalkoxyl,C₃₋₆cycloalkyl, —O—C₃₋₆cycloalkyl, and phenyl. In some embodiments, eachR^(a) is independently selected from F, Cl, OH, CN, —NH₂, —CH₃, —CH₂F,—CHF₂, —CF₃, —OCH₃, and —OCF₃.

In some embodiments of formula (I), (II), (IIa), (IIb), or (IIc), R¹ isselected from

each R¹ is optionally substituted with one to four R^(a). In someembodiments, each R^(a) is independently selected from halo, CN, —OH,NR^(a1)R^(a2), C₁₋₄alkyl, C₁₋₄alkoxyl, C₁₋₄haloalkyl, C₁₋₄haloalkoxyl,C₃₋₆cycloalkyl, —O—C₃₋₆cycloalkyl, and phenyl. In some embodiments, eachR^(a) is independently selected from F, Cl, OH, CN, —NH₂, —NH(CH₃),—N(CH₃)₂, —CH₃, —CH₂F, —CHF₂, —CF₃, —OCH₃, and —OCF₃. In someembodiments, each R^(a) is independently selected from F, Cl, —N(CH₃)₂,—CH₃, —OCH₃, and —CF₃.

In some embodiments of formula (I), (II), (IIa), (IIb), or (IIc), R¹ is

optionally substituted with one to three R^(a). In some embodiments,each R^(a) is independently selected from F, Cl, —N(CH₃)₂, —CH₃, —OCH₃,and —CF₃. In some embodiments, R¹ is substituted with —CH₃.

In some embodiments of formula (I), (II), (IIa), (IIb), or (IIc), R¹ issubstituted with one to three R^(a) independently selected from halo,CN, OH, NR^(a1)R^(a2), C₁₋₄alkyl, C₁₋₄alkoxyl, C₁₋₄haloalkyl,C₁₋₄haloalkoxyl, and C₃₋₆cycloalkyl. In some embodiments, each R^(a) isindependently selected from F, Cl, CN, OH, —NH₂, —N(CH₃)₂, —CH₃,—CH₂CH₃, —CH(CH₃)₂, —C(CH₃)₃, —CH₂CN, —CH₂CH₂CN, —CH₂OH, —CH₂CH₂OH,—OCH₃, —OCH₂CH₃, —OCH(CH₃)₂, —OC(CH₃)₃, —CH₂OCH₃, —CH₂OCH₂CH₃,—CH₂OCH(CH₃)₂, —CH₂F, —CHF₂, —CF₃, —CH₂CH₂F, —CH₂CHF₂, —CH₂CF₃, —OCH₂F,—OCHF₂, —OCF₃, —OCH₂CH₂F, —OCH₂CHF₂, —OCH₂CF₃, —SO₂CH₃, —SO₂CH₂CH₃,

cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, —O—cyclopropyl, —O—CH₂-cyclopropyl, —O-cyclobutyl, —O—CH₂cyclobutyl,—O-cyclopentyl, —O—CH₂cyclopentyl, —O-cyclohexyl, —O—CH₂cyclohexyl, and—O-phenyl. In some embodiments, each R^(a) is independently selectedfrom F, Cl, CN, —NH₂, —CH₃, —CH₂F, —CHF₂, —CF₃, —OCH₃, —CH₂OCH₂CH₃, and—OCF₃.

In some embodiments of formula (I), (II), (IIa), (IIb), or (IIc), R¹ isselected from:

In some embodiments of formula (I), (II), (IIa), (IIb), or (IIc), R¹ isselected from:

In some embodiments of formula (I), (II), (IIa), (IIb), or (IIc), R¹ isselected from

In some embodiments of formula (I), (II), (IIa), (IIb), or (IIc), R¹ isselected from

In some embodiments of formula (I), (II), (IIa), (IIb), or (IIc), R¹ isselected from:

In some embodiments, R¹ is

In some embodiments of formula (I), (II), (IIa), (IIb), or (IIc),“R¹-L-” is —O—C(O)—NR^(a1)R^(a2). In some embodiments, each R^(a1) andR^(a2) is independently selected from H, and C₁₋₄alkyl. In someembodiments, each R^(a1) and R^(a2) is independently selected from H,CH₃, —CH₂CH₃, —CH(CH₃)₂, and —C(CH₃)₃. In some embodiments, each R^(a1)and R^(a2) is independently selected from H, CH₃, and —CH₂CH₃. In someembodiments, both R^(a1) and R^(a2) are CH₃. In some embodiments,“R¹-L-” is —O—C(O)—N(CH₃)₂.

In some embodiments of formula (I), or (II), R² and R³ form aC₃₋₆cycloalkyl, 5-6 membered heterocyclyl, phenyl, or 5-6 memberedheteroaryl. In some embodiments, the 5-6 membered heterocyclyl or 5-6membered heteroaryl comprises one or two N. In some embodiments,C₃₋₆cycloalkyl, 5-6 membered heterocyclyl, phenyl, or 5-6 memberedheteroaryl is substituted with one or two groups independently selectedfrom halo, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₆cycloalkyl, andC₁₋₄alkylene-phenyl. In some embodiments, C₃₋₆cycloalkyl, 5-6 memberedheterocyclyl, phenyl, or 5-6 membered heteroaryl is substituted with oneor two groups independently selected from Cl, —CH₃, cyclopropyl, and—CH₂-phenyl.

In some embodiments of formula (I), or (II), R³ and R⁴ form aC₃₋₆cycloalkyl, 5-6 membered heterocyclyl, phenyl, or 5-6 memberedheteroaryl. In some embodiments, the 5-6 membered heterocyclyl or 5-6membered heteroaryl comprises one or two N. In some embodiments,C₃₋₆cycloalkyl, 5-6 membered heterocyclyl, phenyl, or 5-6 memberedheteroaryl is substituted with one or two groups independently selectedfrom halo, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₆cycloalkyl, andC₁₋₄alkylene-phenyl. In some embodiments, C₃₋₆cycloalkyl, 5-6 memberedheterocyclyl, phenyl, or 5-6 membered heteroaryl is substituted with oneor two groups independently selected from Cl, —CH₃, cyclopropyl, and—CH₂-phenyl.

In some embodiments of formula (I), (II), (IIa), (IIb), (IIc), (IId),(IIg), (IIh), or (IIi), each R², R³, R⁴, R⁵, and R⁶ is independentlyselected from H, halo, CN, OH, —NR^(b1)R^(b2), C₁₋₆alkyl, C₁₋₆alkoxyl,C₁₋₆haloalkyl, and C₁₋₆haloalkoxyl. In some embodiments, each R², R³,R⁴, R⁵, and R⁶ is independently selected from H, halo, CN, OH,—NR^(b1)R^(b2), C₁₋₄alkyl, C₁₋₄alkoxyl, C₁₋₄haloalkyl, andC₁₋₄haloalkoxyl. In some embodiments, each R², R³, R⁴, R⁵, and R⁶ isindependently selected from H, F, Cl, CN, OH, —NH₂, —N(CH₃)₂, —CH₃, CD₃,—CH₂F, —CHF₂, —CF₃, —OCH₃, and —OCF₃. In some embodiments, each R² andR⁶ is independently selected from H, halo, CN, OH, —NR^(b1)R^(b2),C₁₋₄alkyl, C₁₋₄alkoxyl, C₁₋₄haloalkyl, and C₁₋₄haloalkoxyl. In someembodiments, each R² and R⁶ is independently selected from F, Cl, CN,OH, —NH₂, —N(CH₃)₂, —CH₃, —CH₂F, —CHF₂, —CF₃, —OCH₃, and —OCF₃. In someembodiments, both R² and R⁶ are F. In some embodiments, R⁶ is —CH₃. Insome embodiments, each R³ and R⁵ is independently selected from H,C₁₋₆alkyl, C₁₋₆alkoxyl, C₁₋₆haloalkyl, C₁₋₆haloalkoxyl, andC₃₋₆cycloalkyl. In some embodiments, each R³ and R⁵ is independentlyselected from H, C₁₋₄alkyl, C₁₋₄alkoxyl, C₁₋₄ haloalkyl, andC₁₋₄haloalkoxyl. In some embodiments, each R³ and R⁵ is independentlyselected from H, F, —NH₂, —CH₃, —CH₂F, —CHF₂, —CF₃, and —OCH₃. In someembodiments, both R³ and R⁵ are H.

In some embodiments of formula (I), (II), (IIa), (IIb), (IIc), (IId),(IIg), (IIh), or (IIi), R² is F, and R⁶ is —CH₃.

In some embodiments of formula (I), (II), (IId), (IIe), (IIf), (IIg),(IIh), or (IIi), R⁴ is selected from H, —NR^(b1)R^(b2),—NR^(b1)S(O)_(n)R^(b4), and 3-8 membered heterocyclyl. In someembodiments, the 3-8 membered heterocyclyl of R⁴ contains one to twoheteroatoms or groups independently selected from S, N, O, and S(O)₂.

In some embodiments of formula (I), (II), (IId), (IIe), (IIf), (IIg),(IIh), or (IIi), R⁴ is —NR^(b1)R^(b2). In some embodiments, each R^(b1)and R^(b2) is independently selected from H, C₁₋₈alkyl, C₁₋₈haloalkyl,C₃₋₆cycloalkyl, phenyl, and 3-8 membered heterocyclyl. In someembodiments, 3-8 membered heterocyclyl contains one to two atomsindependently selected from N and O. In some embodiments, R^(b1) isselected from H, C₁₋₄alkyl, and C₁₋₆haloalkyl. In some embodiments,R^(b1) is selected from H, and CH₃. In some embodiments, R^(b2) isselected from C₁₋₆alkyl, C₁₋₈haloalkyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkyl,and 4-6 membered heterocyclyl. In some embodiments, R^(b2) is selectedfrom C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₆cycloalkyl, and 4-6 memberedheterocyclyl. In some embodiments, R^(b1) is H, and R^(b2) is selectedfrom C₁₋₆alkyl, C₁₋₈haloalkyl, C₃₋₆cycloalkyl, and 5-6 memberedheterocyclyl. In some embodiments, R^(b1) is H, and R^(b2) isC₁₋₆haloalkyl. In some embodiments, R^(b2) is —C₁₋₅alkylene-CF₃. In someembodiments, R^(b2) is selected from -methylene-CF₃, -ethylene-CF₃,-propylene-CF₃, -butylene-CF₃, and -pentylene-CF₃. In some embodiments,R^(b2) is —C₁₋₅alkylene-CF₃ substituted with one or two R^(b5). In someembodiments, each R^(b5) is independently selected from hydroxyl,C₁₋₄alkoxyl, C₃₋₆cycloalkyl, phenyl, and 4-6 membered heterocyclyl. Insome embodiments, each R^(b5) is independently selected fromC₃₋₆cycloalkyl, 4-6 membered heterocyclyl, and phenyl. EachC₁₋₆cycloalkyl, 4-6 membered heterocyclyl, and phenyl of R^(b5) isindependently optionally substituted with one or three groupsindependently selected from halo, hydroxyl, cyano, —NR^(b1)R^(b2),C₁₋₄alkyl, C₁₋₄alkoxyl, and C₁₋₄haloalkyl. In some embodiments, R^(b5)is selected from cyclopropyl, cyclobutyl, cylcopentyl,tetrahydropyranyl, tetrahydrofuranyl, and phenyl; and each R^(b5) isoptionally substituted with one group selected from F, Cl, CN, —CH₃,—CH₂F, —CHF₂, and —CF₃. In some embodiments, R^(b5) is phenyl. In someembodiments, R^(b5) is phenyl substituted with one or two groupsindependently selected from F, Cl, CN, —CH₃, —CH₂F, —CHF₂, and —CF₃. Insome embodiments, R^(b5) is phenyl substituted with one or two groupsindependently selected from F, Cl, CN, and —CF₃. In some embodiments,R^(b)5 is unsubstituted phenyl.

In some embodiments of formula (I), (II), (IId), (IIe), (IIf), (IIg),(IIh), or (IIi), R⁴ is selected from

In some embodiments of formula (I), (II), (IId), (IIe), (IIf), (IIg),(IIh), or (IIi), R⁴ is selected from

In some embodiments formula (I), (II), (IId), (IIe), (IIf), (IIg),(IIh), or (IIi), R⁴ is

In some embodiments of formula (I), (II), (IId), (IIe), (IIf), (IIg),(IIh), or (IIi), R⁴ is 3-8 membered heterocyclyl optionally substitutedwith one to three R^(b); and each R^(b) is independently selected fromhalo, hydroxyl, cyano, —NR^(a1)R^(a2), C₁₋₄alkyl, C₁₋₄alkoxyl, andC₁₋₄haloalkyl. In some embodiments, each R⁴ is optionally substitutedwith one to two groups independently selected from F, Cl, CN, —OH, —CH₃,—CH(CH₃)₂, and —CF₃.

In some embodiments of formula (I), (II), (IId), (IIe), (IIf), (IIg),(IIh), or (IIi), R⁴ is 3-8 membered spiro, fused or bridgedheterocyclyl. In some embodiments, R⁴ is selected from azetidinyl,aziridinyl, imidazolidinyl, morpholinyl, oxetanyl, piperazinyl,piperidinyl, pyrazolidinyl, piperidinyl, pyrrolidinyl, pyrrolidinonyl,tetrahydrofuranyl, tetrahydrothiophenyl, dihydropyridinyl,tetrahydropyridinyl, 1,1-dioxide-thiomorpholinyl, and quinuclidinyl; andeach R⁴ is optionally substituted with one to three R^(b). In someembodiments, R⁴ is selected from morpholinyl, piperidinyl,tetrahydropyranyl, and pyrrolidinyl; each R⁴ is optionally substitutedwith one to three R^(b). In some embodiments, each R^(b) isindependently selected from halo, hydroxyl, cyano, —NR^(a1)R^(a2),C₁₋₄alkyl, C₁₋₄alkoxyl, and C₁₋₄haloalkyl. In some embodiments, eachR^(b) is independently selected from F, Cl, CN, —OH, —CH₃, —CH(CH₃)₂,and —CF₃.

In some embodiments of formula (I), (II), (IId), (IIe), (IIf), (IIg),(IIh), or (IIi), R⁴ is a spirocyclyl optionally substituted with one tothree R^(b). In some embodiments, R⁴ is aza spiroheptanyl. In someembodiments, R⁴ is azaspiro[3.3]heptanyl. In some embodiments, R⁴ isazaspiro[2.4]heptanyl. In some embodiments, each R^(b) is independentlyselected from halo, hydroxyl, cyano, —NR^(a1)R^(a2), C₁₋₄alkyl,C₁₋₄alkoxyl, and C₁₋₄haloalkyl. In some embodiments, each R^(b) isindependently selected from F, Cl, CN, —OH, —CH₃, —CH(CH₃)₂, and —CF₃.

In some embodiments of formula (I), (II), (IId), (IIe), (IIf), (IIg),(IIh), or (IIi), R⁴ is a fused or bridged heterocyclyl optionallysubstituted with one to three R^(b). In some embodiments, each R⁴ isindependently selected from azabyicyclo[3.1.0]hexanyl,azabyicyclo[3.2.1]octanyl, azabyicyclo[2.2.2] octanyl, andoxa-azabicyclo[2.2.2]octanyl; each R⁴ is optionally substituted with oneto three R^(b). Each R^(b) is independently selected from halo,hydroxyl, cyano, —NR^(a1)R^(a2), C₁₋₄alkyl, C₁₋₄alkoxyl, andC₁₋₄haloalkyl. In some embodiments, each R^(b) is independently selectedfrom F, Cl, CN, —OH, —CH₃, —CH(CH₃)₂, and —CF₃.

In some embodiments of formula (I), (II), (IId), (IIe), (IIf), (IIg),(IIh), or (IIi), R⁴ is selected from

and each R⁴ is optionally substituted with one to three groupsindependently selected from halo, OH, CN, —NR^(a1)R^(a2), C₁₋₄alkyl,C₁₋₄alkoxyl, and C₁₋₄haloalkyl.

In some embodiments of formula (I), (II), (IId), (IIe), (IIf), (IIg),(IIh), or (IIi), R⁴ is selected from

and each R⁴ is optionally substituted with one to three groupsindependently selected from F, Cl, OH, CN, NH₂, —CH₃, —CH(CH₃)₂, —CH₂F,—CHF₂, —CF₃, —CH₂CH₂F, —CH₂CHF₂, —CH₂CF₃, C₃₋₆cycloalkyl, and—CH₂C₃₋₆cycloalkyl.

In some embodiments of formula (I), (II), (IId), (IIe), (IIf), (IIg),(IIh), or (IIi), R⁴ is selected from

In some embodiments of formula (I), (II), (IId), (IIe), (IIf), (IIg),(IIh), or (IIi), R⁴ is selected from

In some embodiments of formula (I), (II), (IId), (IIe), (IIf), (IIg),(IIh), or (IIi), R⁴ is selected from

In some embodiments, R⁴ is

In some embodiments of formula (I), (II), (IId), (IIe), (IIf), (IIg),(IIh), or (IIi), R⁴ is —NHS(O)₂R^(b4). In some embodiments, R^(b4) isselected from C₁₋₄alkyl, C₁₋₄haloalkyl, C₃₋₆cycloalkyl, and phenyl. Insome embodiments, R^(b4) is selected from —CH₃, —CH₂F, —CHF₂, —CF₃, andphenyl. In some embodiments, phenyl is optionally substituted withpyridinyl that is optionally substituted with one or two groupsindependently selected from halo, and C₁₋₄alkyl. In some embodiments,the pyridinyl is optionally substituted with one or two groupsindependently selected from F, and —CH₃.

In some embodiments of formula (I), (II), (IId), (IIe), (IIf), (IIg),(IIh), or (IIi), R⁴ is selected from

In some embodiments of formula (IIb), X¹ is CH or N. In someembodiments, X¹ is N. In some embodiments, X² is selected from CH₂,NR^(x), O, and S(O)₂. In some embodiments, X¹ is N, and X² is O. In someembodiments, X¹ is N, and X² is CH₂. In some embodiments, X¹ is N, andX² is S(O)₂. In some embodiments, each R^(b) is independently selectedfrom F, OH, —CH₃, —CH(CH₃)₂, —CH₂F, —CHF₂, and —CF₃.

In some embodiments of formula (IIb), p is 0. In some embodiments, pis 1. In some embodiments, p is 2. In some embodiments, q is 1. In someembodiments, q is 2.

In some embodiments of formula (IId), Y¹, Y², Y³, Y⁴, and Y⁵ are CR^(y).In some embodiments, at least one of Y¹, Y², Y³, Y⁴, and Y⁵ is N. Insome embodiments, Y¹ is N; and Y², Y³, Y⁴, and Y⁵ are CR^(y). In someembodiments, Y² is N; and Y¹, Y³, Y⁴, and Y⁵ are CR^(y). In someembodiments, Y³ is N; and Y¹, Y², Y⁴, and Y⁵ are CR^(y). In someembodiments, Y¹ and Y⁵ are N; and Y¹, Y², and Y³ are CR^(y).

In some embodiments of formula (IId), (IIf), (IIg), or (IIh), each R^(y)is independently selected from H, halo, hydroxyl, CN, —NR^(a1)R^(a2),C₁₋₄alkyl, C₁₋₄alkoxyl, and C₁₋₄haloalkyl. In some embodiments, eachR^(y) is independently selected from H, F, Cl, CN, OH, —NH₂, —N(CH₃)₂,—CH₃, —CH₂CH₃, —CH(CH₃)₂, —C(CH₃)₃, —CH₂CN, —CH₂CH₂CN, —CH₂OH,—CH₂CH₂OH, —OCH₃, —OCH₂CH₃, —OCH(CH₃)₂, —OC(CH₃)₃, —CH₂OCH₃,—CH₂OCH₂CH₃, —CH₂OCH(CH₃)₂, —CH₂F, —CHF₂, —CF₃, —CH₂CH₂F, —CH₂CHF₂,—CH₂CF₃, —OCH₂F, —OCHF₂, —OCF₃, —OCH₂CH₂F, —OCH₂CHF₂, —OCH₂CF₃, —SO₂CH₃,—SO₂CH₂CH₃,

cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl,—O-cyclopropyl, —O—CH₂-cyclopropyl, —O— cyclobutyl, —O—CH₂cyclobutyl,—O-cyclopentyl, —O—CH₂cyclopentyl, —O-cyclohexyl, —O—CH₂cyclohexyl, and—O-phenyl. In some embodiments, each R^(y) is independently selectedfrom H, F, Cl, OH, CN, —NH₂, —CH₃, —CH₂F, —CHF₂, —CF₃, —OCH₃,—CH₂OCH₂CH₃, and —OCF₃. In some embodiments, each R^(y) is independentlyselected from H, F, —CH₃, —CH₂F, —CHF₂, —CF₃, —OCH₃, —CH₂OCH₂CH₃, and—OCF₃.

In some embodiments of formula (IIe), u is selected from 1, 2, and 3. Insome embodiments, u is 3.

In some embodiments of formula (IIg), Y³, Y⁴, and Y⁵ is independentlyselected from CR^(y), and N; wherein R^(y) is selected from H, andR^(a). In some embodiments, Y³ is N; and Y⁴ and Y⁵ are CR^(y). In someembodiments, Y⁵ is N; and Y³, and Y⁴ are CR^(y). In some embodiments,each R^(y) is independently selected from H, F, Cl, CN, —NH₂, —N(CH₃)₂,—CH₃, —CH₂F, —CHF₂, —CF₃, and —OCH₃. In some embodiments, each Rx isindependently selected from H, F, Cl, —NH₂, —N(CH₃)₂, —CH₃, —CF₃, —OCH₃,and —OCF₃.

In some embodiments of formula (IIi), r is selected from 1, 2, and 3. Insome embodiments, r is 3.

In some embodiments of formula (I) or (II), each R⁷, R⁸, R⁹, R¹⁰, andR¹¹ is independently selected from H, F, Cl, CN, —NH₂, —N(CH₃)₂, —CH₃,—CH₂F, —CHF₂, —CF₃, —OCH₃, and —OCF₃. In some embodiments, each R⁷, R⁸,R⁹, R¹⁰, and R¹¹ is selected from H, F, CN, —N(CH₃)₂, —CH₃, and —CF₃. Insome embodiments, each R⁷ to R¹¹ is selected from H, F, and —N(CH₃)₂. Insome embodiments, R⁷ to R¹¹ are H. In some embodiments, R⁷ is selectedfrom H, F, CN, —N(CH₃)₂, —CH₃, and —CF₃. In some embodiments, R⁷ is F.In some embodiments, R⁸ is selected from H, F, CN, —N(CH₃)₂, —CH₃, and—CF₃. In some embodiments, R⁸ is F. In some embodiments, R¹⁰ is selectedfrom H, F, CN, —N(CH₃)₂, —CH₃, and —CF₃. In some embodiments, R¹⁰ is F,or —N(CH₃)₂. In some embodiments, R¹¹ is —CH₃.

In some embodiments of formula (I), R¹² is H. In some embodiments, R¹²is —CH₃.

In some embodiments of formula (I), R¹³ is H. In some embodiment, R¹³ is—CH₃.

In some embodiments of formula (I), each R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², andR¹³ is H.

In some embodiments of formula (I), (II), (IIa), (IIb), (IIc), (IId),(IIe), (IIf), (IIg), (IIh), or (IIi), R¹⁴ is selected from C₁₋₆alkyl,C₃₋₈cycloalkyl, and 4-6 membered heterocyclyl. In some embodiments, eachC₃₋₈cycloalkyl and 4-6 membered heterocyclyl of R¹⁴ is optionallysubstituted with one to three groups independently selected from halo,C₁₋₄alkyl, and C₁₋₄haloalkyl. In some embodiments, R¹⁴ is selected from—C₁₋₄alkylene-NR^(a1)R^(a2), —C₁₋₄alkylene-C(O)NR^(a1)R^(a2),—C₁₋₄alkylene-O—C(O)—C₁₋₄alkyl, —C₁₋₄alkylene-O—C(O)—O—C₁₋₄alkyl,—C₁₋₄alkylene-O—C(O)—C₁₋₄alkylene-NR^(a1)R^(a2), and—C₁₋₄alkylene-O—C₁₋₄alkyl. In some embodiments, when administered to abiological system, provided esters generate active ingredients where R¹⁴is hydrogen, as a result of chemical reaction(s), enzyme catalyzedchemical reaction(s), and/or metabolic chemical reaction(s).

In some embodiments of formula (I), (II), (IIa), (IIb), (IIc), (IId),(IIe), (IIf), (IIg), (IIh), or (IIi), R¹⁴ is selected from H, methyl,ethyl, propyl, butyl, —CH₂C(O)N(CH₃)₂, —(CH₂)₂N(CH₂CH₃)₂,—CH₂—O—C(O)CH₃, —(CH₂)₂—O—C(O)CH₃, —CH₂—O—C(O)C(CH)₃,—(CH₂)₂—O—C(O)C(CH)₃, —CH₂—O—C(O)—O—CH₃, —CH(CH₃)—O—C(O)—O—CH₃,—CH₂—O—C(O)—O—CH₂CH₃, —CH₂—O—C(O)—O—CH(CH₃)₂, —CH₂—O—C(O)—O—C(CH₃)₃,—(CH₂)₂C(O)CH₃,

In some embodiments, R¹⁴ is selected from H, —CH₂—O—C(O)C(CH)₃,—CH(CH₃)—O—C(O)—O—CH₃,

In some embodiments, R¹⁴ together with the N that attaches to R¹³ formsa 5 membered heterocyclyl. In some embodiments, the 5 memberedheterocyclyl is substituted with one to two groups independentlyselected from C₁₋₆alkyl, C₁₋₆alkoxyl, C₁₋₆haloalkyl, and C₆₋₁₀aryl. Insome embodiments, the 5 membered heterocyclyl is substituted with one totwo groups independently selected from CH₃, CH₂CH₃, —OCH₃, —OCH₂CH₃, andphenyl. In some embodiments, the 5 membered heterocyclyl is substitutedwith phenyl, and phenyl is optionally substituted with one to threegroups independently selected from halo, C₁₋₆alkyl, C₁₋₆alkoxyl, andC₁₋₆haloalkyl.

In some embodiments, R¹⁴ is H.

In some embodiments, R¹⁴ is CH₃, or CH₂CH₃. In some embodiments, R¹⁴ isCH₃. In some embodiments, R¹⁴ is CH₂CH₃.

In some embodiments, the compound of the present disclosure is selectedfrom examples 1-354.

In some embodiments, the compound of the present disclosure is selectedfrom examples 355-406. In some embodiments, the compound of the presentdisclosure is selected from examples 407-496.

In some embodiments, the compound of the present disclosure is selectedfrom:

In another aspect, provided are compounds of Formula (J), orpharmaceutically acceptable salts thereof:

or a pharmaceutically acceptable salt thereof, wherein:

L is selected from a bond, —O—, —O—C(O)—*, —NH—, —C(O)—N(H)—*, and—N(H)—C(O)—*; wherein * indicates the point of attachment of L to R¹;

R¹ is selected from A¹, A², A³, and A⁴;

-   -   A¹ is 5-10 membered heteroaryl containing one to five        heteroatoms independently selected from S, N, and O; wherein A¹        optionally comprises one to three C(O); and wherein A¹ is        optionally substituted with one to six R^(a);    -   A² is C₆₋₁₀aryl, optionally substituted with one to six R^(a);        -   A³ is C₅₋₁₀cycloalkyl or 5-14 membered heterocyclyl; wherein            A³ is optionally substituted with one to four groups            independently selected from oxo and R^(a); and        -   A⁴ is —NR^(a1)R^(a2).        -   wherein each R^(a) is independently selected from halo,            cyano, hydroxyl, —NR^(a1)R^(a2), C₁₋₆alkyl, C₂₋₆alkenyl,            C₂₋₆alkynyl, C₁₋₆alkoxyl, C₁₋₆haloalkyl, C₁₋₆haloalkoxyl,            —S(O)_(m)—C₁₋₆alkyl, C₃₋₈cycloalkyl, 3-6 membered            heterocyclyl, C₆₋₁₀aryl, 5-6 membered heteroaryl,            —O—C₃₋₈cycloalkyl, —O-(3-6 membered heterocyclyl),            —O—C₁₋₄alkylene-C₃₋₈cycloalkyl, and —O-phenyl;            -   wherein each C₃₋₈cycloalkyl, 3-6 membered heterocyclyl,                C₆₋₁₀aryl, 5-6 membered heteroaryl, —O—C₃₋₈cycloalkyl,                —O-(3-6 membered heterocyclyl),                —O—C₁₋₄alkylene-C₃₋₈cycloalkyl, and —O-phenyl of R^(a)                is independently optionally substituted with one to                three groups independently selected from halo, cyano,                hydroxyl, —NR^(a1)R^(a2), C₁₋₆alkyl, C₁₋₆haloalkyl,                C₁₋₆alkoxyl, and C₁₋₆haloalkoxyl; and            -   wherein each C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,                C₁₋₆alkoxyl, C₁₋₆haloalkyl, C₁₋₆haloalkoxyl, and                —S(O)_(m)—C₁₋₆alkyl of R^(a) is optionally substituted                with one to three R^(a3), wherein each R^(a3) is                independently selected from halo, cyano, hydroxyl,                —NR^(a1)R^(a2), C₁₋₆alkoxyl, C₃₋₈cycloalkyl, and 3-6                membered heterocyclyl;            -   wherein each C₃₋₈cycloalkyl and 3-6 membered                heterocyclyl of R^(a3) is optionally substituted with                one to three R^(a4); and each R^(a4) is independently                selected from halo, cyano, hydroxyl, —NR^(a1)R^(a2),                C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxyl, C₁₋₆haloalkoxyl,                C₃₋₈cycloalkyl, and 3-6 membered heterocyclyl;

each R², R³, R⁴, R⁵, and R⁶ is independently selected from H, halo,cyano, hydroxyl, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxyl,C₁₋₈haloalkyl, C₁₋₈haloalkoxyl, —NR^(b1)R^(b2), —R^(b3)S(O)_(m)R^(b4),—S(O)_(m)R^(b4), —NR^(b1)S(O)_(n)R^(b4), —COOR^(b1), —CONR^(b1)R^(b2),—NR^(b1)COOR^(b2), —NR^(b1)COR^(b4), —R^(b3)NR^(b1)R^(b2),—S(O)_(n)NR^(b1)R^(b2), C₃₋₁₂cycloalkyl, C₆₋₁₀aryl, 5-6 memberedheteroaryl, and 3-12 membered heterocyclyl;

-   -   wherein each C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxyl,        C₁₋₈haloalkyl, and C₁₋₆haloalkoxyl of R², R³, R⁴, R⁵, and R⁶ is        optionally substituted with one to two R^(c); wherein each R^(c)        is independently selected from azido, oxo, cyano, halo,        hydroxyl, —NR^(a1)R^(a2), C₁₋₄alkoxyl, C₃₋₈cycloalkyl,        C₆₋₁₀aryl, 5-6 membered heteroaryl, and 4-6 membered        heterocyclyl; wherein each C₃₋₈cycloalkyl, C₆₋₁₀aryl, 5-6        membered heteroaryl, and 4-6 membered heterocyclyl of R^(c) is        optionally substituted with one to three groups independently        selected from halo, cyano, hydroxyl, —NR^(a1)R^(a2), C₁₋₄alkyl,        C₁₋₆haloalkyl, C₁₋₄alkoxyl, and C₃₋₆cycloalkyl;    -   wherein each C₆₋₁₀aryl, and 5-6 membered heteroaryl of R², R³,        R⁴, R⁵, and R⁶ is independently optionally substituted with one        to five R^(b); and    -   wherein each C₃₋₁₂cycloalkyl, and 3-12 membered heterocyclyl of        R², R³, R⁴, R⁵, and R⁶ is independently optionally substituted        with one to six groups independently selected from        ═CR^(b1)R^(b2) and R^(b);        -   wherein each R^(b) is independently selected from azido,            cyano, halo, hydroxyl, —NR^(a1)R^(a2), C₁₋₆alkyl,            C₁₋₈haloalkyl, C₁₋₆alkoxyl, C₃₋₆cycloalkyl, C₆₋₁₀aryl, 5-6            membered heteroaryl, and 4-6 membered heterocyclyl; wherein            each C₃₋₆cycloalkyl, C₆₋₁₀aryl, 5-6 membered heteroaryl, and            4-6 membered heterocyclyl of R^(b) is independently            optionally substituted with one to three groups            independently selected from halo, cyano, hydroxyl,            —NR^(a1)R^(a2), C₁₋₄alkyl, C₁₋₄haloalkyl, and C₁₋₄alkoxyl;        -   wherein each R^(b1) and R^(b2) is independently selected            from H, C₁₋₈alkyl, C₁₋₈haloalkyl, C₃₋₈cycloalkyl, C₆₋₁₀aryl,            5-6 membered heteroaryl, and 3-8 membered heterocyclyl;            -   wherein each C₃₋₈cycloalkyl, C₆₋₁₀aryl, 5-6 membered                heteroaryl, and 4-6 membered heterocyclyl of R^(b1) and                R^(b2) is independently optionally substituted with one                to three groups independently selected from halo, cyano,                hydroxyl, —NR^(a1)R^(a2), C₁₋₈alkyl, C₁₋₈haloalkyl,                C₁₋₆alkoxyl, C₃₋₆cycloalkyl, C₆₋₁₀aryl, 5-6 membered                heteroaryl, and 4-6 membered heterocyclyl; and            -   wherein each C₁₋₈alkyl and C₁₋₈haloalkyl of R^(b1) and                R^(b2) is optionally substituted with one to two R^(b5);        -   wherein R^(b3) is C₁₋₄alkylene;        -   wherein R^(b4) is selected from C₁₋₄alkyl, C₁₋₄haloalkyl,            C₃₋₆cycloalkyl, C₆₋₁₀aryl, 5-6 membered heteroaryl, and 4-6            membered heterocyclyl; wherein each C₁₋₄alkyl,            C₁₋₄haloalkyl, C₃₋₈cycloalkyl, C₆₋₁₀aryl, 5-6 membered            heteroaryl, and the 4-6 membered heterocyclyl of R^(b4) is            optionally substituted with one to three R^(b6);        -   wherein each R^(b5) is independently selected from cyano,            hydroxyl, C₁₋₄alkoxyl, C₃₋₈cycloalkyl, C₆₋₁₀aryl, 5-6            membered heteroaryl, and 4-6 membered heterocyclyl; and each            C₁₋₄alkoxyl, C₃₋₈cycloalkyl, C₆₋₁₀aryl, 5-6 membered            heteroaryl, and 4-6 membered heterocyclyl of R^(b5) is            optionally substituted with one to three groups            independently selected from halo, cyano, hydroxyl,            —NR^(a1)R^(a2), C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxyl, and            phenyl; and        -   wherein each R^(b6) is independently selected from halo,            cyano, C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxyl,            C₃₋₆cycloalkyl, phenyl, 4-6 membered heterocyclyl, and 5-6            membered heteroaryl; wherein each C₃₋₆cycloalkyl, 4-6            membered heterocyclyl, and 5-6 membered heteroaryl of R^(b6)            is independently optionally substituted with one to three            groups independently selected from halo, cyano,            —NR^(a1)R^(a2), C₁₋₄alkyl, C₁₋₄haloalkyl, and C₁₋₄alkoxyl;            or    -   R² and R³, R³ and R⁴, or R⁵ and R⁶ together with the atoms to        which they are attached form a C₆₋₁₀aryl, 5-6 membered        heteroaryl, C₃₋₆cycloalkyl, or 5-6 membered heterocyclyl;        wherein each C₆₋₁₀aryl, 5-6 membered heteroaryl, C₃₋₆cycloalkyl,        and 5-6 membered heterocyclyl is independently optionally        substituted with one to three groups independently selected from        halo, cyano, —NR^(a1)R^(a2), C₁₋₆alkyl, C₁₋₆alkoxyl,        C₁₋₆haloalkyl, C₃₋₈cycloalkyl, 3-6 membered heterocyclyl,        C₆₋₁₀aryl, 5-6 membered heteroaryl, C₁₋₄        alkylene-C₃₋₈cycloalkyl, C₁₋₄alkylene-C₆₋₁₀aryl, and        C₁₋₄alkylene-(5-6 membered heteroaryl);

each R⁷, R⁸, R⁹, R¹⁰, R¹¹, and R¹² is independently selected from H,halo, hydroxyl, cyano, C₁₋₆alkyl, C₁₋₆alkoxyl, C₁₋₆haloalkyl,C₁₋₆haloalkoxyl, and —NR^(a1)R^(a2);

R¹³ is selected from H, C₁₋₄alkyl, and C₁₋₄haloalkyl;

R¹⁵ is selected from H, C₁₋₁₀alkyl, C₁₋₁₀haloalkyl, C₃₋₁₀cycloalkyl,3-14 membered heterocyclyl, C₆₋₁₀aryl, 5-10 membered heteroaryl,—C₁₋₄alkylene-NR^(a1)R^(a2), —C₁₋₄alkylene-C(O)NR^(a1)R^(a2), and-L¹-R¹⁶;

-   -   wherein L¹ is selected from —C₁₋₄alkylene-, —C₁₋₄alkylene-O—,        —C₁₋₄alkylene-C(O)—, —C₁₋₄ alkylene-O—C(O)—,        —C₁₋₄alkylene-O—C(O)—C₁₋₄alkylene-, —C₁₋₄alkylene-C(O)—O—,        —C₁₋₄alkylene-C(O)—O—C₁₋₄alkylene, —C₁₋₄alkylene-O—C(O)—O—,        —C₁₋₄alkylene-O—C(O)—O—C₁₋₄alkylene-,        —C₁₋₄alkylene-NR^(a1)C(O)—O—, and —C₁₋₄alkylene-O—C(O)—NR^(a1)—;        and    -   wherein R¹⁶ is selected from C₁₋₆alkyl, C₁₋₆haloalkyl,        C₃₋₁₀cycloalkyl, 3-14 membered heterocyclyl, C₆₋₁₀aryl, and 5-10        membered heteroaryl;    -   wherein each C₃₋₁₀cycloalkyl, 3-14 membered heterocyclyl,        C₆₋₁₀aryl, and 5-10 membered heteroaryl of R¹⁵ and R¹⁶ is        optionally substituted with one to four groups independently        selected from halo, hydroxyl, —COOR^(b7), —NR^(a1)R^(a2),        —S(O)₂R^(a5), C₁₋₄alkyl, C₁₋₄alkoxyl, C₁₋₄haloalkyl,        C₁₋₄haloalkoxyl, and —C₁₋₄alkylene-NR^(a1)R^(a2);

each R^(a1) and R^(a2) is independently selected from H, C₁₋₆alkyl, andC₁₋₆haloalkyl;

R^(a5) is C₁₋₆alkyl;

R^(b7) is independently selected from H and C₁₋₆alkyl;

m is selected from 0, 1, and 2; and

n is selected from 1, and 2.

In some embodiments of formula (J), or a pharmaceutically acceptablesalt thereof, wherein the compound is of formula (Ja):

wherein each Y¹, Y², Y³, and Y⁴ is independently selected from CR^(y),and N; wherein each R^(y) is independently selected from H and R^(a);and wherein R^(z) is selected from H, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, and 3-6 memberedheterocyclyl.

In some embodiments of formula (J) or (Ja), or a pharmaceuticallyacceptable salt thereof, wherein the compound is of formula (Jb):

wherein each Y² and Y⁴ is independently selected from CR^(y), and N.Each R^(y) is independently selected from H and R^(a). R^(z) is selectedfrom H, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,C₃₋₈cycloalkyl, and 3-6 membered heterocyclyl. X¹ is selected fromCR^(x1), and N. X² is selected from CR^(x1)R^(x2), NR^(x2), O, andS(O)₂. Rx is selected from H, and R^(b); and R^(x2) is selected from H,C₁₋₄alkyl, and C₁₋₄haloalkyl. q is selected from 0, 1, 2, and 3; and ris selected from 0, 1, and 2.

In some embodiments of formula (J) or (Ja), or a pharmaceuticallyacceptable salt thereof, wherein the compound is of formula (Jc):

wherein R^(Z) is selected from H, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆haloalkyl, C₃₋₈cycloalkyl, and 3-6 membered heterocyclyl; andwherein r is selected from 0, 1, 2, and 3.

In some embodiments of formula (J), (Ja), (Jb), or (Jc), or apharmaceutically acceptable salt thereof, wherein the compound is offormula (Jd):

wherein R^(z) is selected from H, —CH₃, —CD₃-CH₂F, —CHF₂, —CF₃, and—CH₂CH₃; X¹ is selected from CR^(x1), and N. X² is selected fromCR^(x1)R^(x2), NR^(x2), O, and S(O)₂. R^(x1) is selected from H, andR^(b); and R^(x2) is selected from H, C₁₋₄alkyl, and C₁₋₄haloalkyl. q isselected from 0, 1, 2, and 3; and r is selected from 0, 1, 2, and 3.

In some embodiments of formula (J), (Ja), (Jb), (Jc), or (Jd), or apharmaceutically acceptable salt thereof, wherein the compound is offormula (Je):

wherein X¹ is selected from CR^(x1), and N. X² is selected fromCR^(x1)R^(x2), NR^(x2), O, and S(O)₂. R^(x1) is selected from H, andR^(b); and R^(x2) is selected from H, C₁₋₄alkyl, and C₁₋₄haloalkyl. q isselected from 0, 1, 2, and 3.

In some embodiments of formula (J), or (Ja), or a pharmaceuticallyacceptable salt thereof, wherein the compound is of formula (Jf):

wherein each Y¹ and Y⁴ is independently selected from CR^(y), and N.Each R^(y) is independently selected from H and R^(a). R^(z) is selectedfrom H, —CH₃, —CD₃-CH₂F, —CHF₂, —CF₃, and —CH₂CH₃. X¹ is selected fromCR^(x1), and N. X² is selected from CR^(x1)R^(x2), NR^(x2), O, andS(O)₂. R^(x1) is selected from H, and R^(b); and R^(x2) is selected fromH, C₁₋₄alkyl, and C₁₋₄haloalkyl. q is selected from 0, 1, 2, and 3; andr is selected from 0, 1, and 2.

In some embodiments of formula (J), or a pharmaceutically acceptablesalt thereof, wherein the compound is of formula (Jg):

wherein each Z¹, Z², Z³, and Z⁴ is independently selected fromCR^(y1)R^(y2), NR^(z1), and O; wherein each R^(y1) and R^(y2) isindependently selected from H and R^(a); and wherein each R^(z) andR^(z1) is independently selected from H, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, and 3-6 memberedheterocyclyl.

In some embodiments of formula (I), or (J), or a pharmaceuticallyacceptable salt thereof, R¹ is selected from

wherein each R¹ is substituted with one to four R^(a). In someembodiments, R^(a) is C₁₋₄alkyl. In some embodiments, R^(a) is —CH₃. Insome embodiments, R¹ is selected from

In some embodiments of formula (I) or (J), or a pharmaceuticallyacceptable salt thereof, R¹ is selected from

each R¹ is optionally substituted with one to four R^(a). In someembodiments, each R^(a) is independently selected from halo, CN, —OH,NR^(a1)R^(a2), C₁₋₄alkyl, C₁₋₄alkoxyl, C₁₋₄haloalkyl, C₁₋₄haloalkoxyl,C₃₋₆cycloalkyl, —O—C₃₋₆cycloalkyl, and phenyl. In some embodiments, eachR^(a) is independently selected from F, Cl, OH, CN, —NH₂, —NH(CH₃),—N(CH₃)₂, —CH₃, —CH₂F, —CHF₂, —CF₃, —OCH₃, and —OCF₃. In someembodiments, each R^(a) is independently selected from —N(CH₃)₂, —CH₃,—OCH₃, and —CF₃.

In some embodiments of formula (I), or (J), R¹ is selected from:

In some embodiments, R¹ is

In some embodiments of formula (I), or (J), or a pharmaceuticallyacceptable salt thereof, R¹ is

substituted with one to two R^(a). Each R^(a) is independently selectedfrom C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxyl, and C₃₋₆cycloalkyl. In someembodiments, R¹ is

In some embodiments of formula (J), (Ja), or (Jc), or a pharmaceuticallyacceptable salt thereof, R³ and R⁵ are H.

In some embodiments of formula (J), (Ja), (Jb), (Jc), (Jd), (Je), or(Jf), or a pharmaceutically acceptable salt thereof, each R² and R⁶ isindependently selected from H, halo, C₁₋₄alkyl, C₁₋₄alkoxyl,C₁₋₄haloalkyl, C₁₋₄haloalkoxyl, C₃₋₆cycloalkyl, and 3-7 memberedheterocyclyl. In some embodiments, each R² and R⁶ is independentlyselected from F, Cl, —CH₃, —CD₃, —CH₂CH₃, —OCH₃, —OCH₂CH₃, —CH₂F, —CHF₂,—CF₃, —CH₂CH₂F, —CH₂CHF₂, —CH₂CF₃, —NH₂, and —N(CH₃)₂. In someembodiments, each R² and R⁶ is independently selected from F, Cl, and—CH₃. In some embodiments, R² is F, and R⁶ is —CH₃. In some embodiments,each R² and R⁶ is independently selected from F, and Cl. In someembodiments, R² and R⁶ are F.

In some embodiments of formula (J), (Ja), (Jb), (Jc), (Jd), (Je), or(Jf), or a pharmaceutically acceptable salt thereof, R⁴ is

substituted with one to three R^(b). In some embodiments, each R^(b) isindependently selected from C₁₋₄alkyl, C₁₋₄alkoxyl, C₁₋₄haloalkyl, andC₁₋₄haloalkoxyl. In some embodiments, R^(b) is independently selectedfrom —CH₃, —CF₃, and —OCF₃. In some embodiments, R^(b) is —CF₃. In someembodiments, R⁴ is

In some embodiments of formula (Ja) or (Jb), Y² is N. In someembodiments of formula (Ja) or (Jb), Y² is N, and Y⁴ is CH. In someembodiments of formula (Ja), Y¹, Y³, and Y⁴ are CR^(y). In someembodiments of (Ja), at least one of Y¹, Y², Y³, and Y⁴ is N. In someembodiments, Y⁴ is CH. In some embodiments of (Ja), Y¹, Y², Y³, and Y⁴are CR^(y).

In some embodiments of formula (Jf), Y¹ is N. In some embodiments, Y⁴ isN. In some embodiments, both Y¹ and Y⁴ are N.

In some embodiments of formula (Ja), (Jb), (Jc), (Jd), or (Jf), or apharmaceutically acceptable salt thereof, R^(z) is —CH₃.

In some embodiments of formula (Jb), (Jd), (Je), or (Jf), or apharmaceutically acceptable salt thereof, X¹ is N.

In some embodiments of formula (Jb), (Jd), (Je), or (Jf), or apharmaceutically acceptable salt thereof, X² is O. In some embodiments,X¹ is N, and X² is O.

In some embodiments of formula (Jb), (Jd), (Je), or (Jf), or apharmaceutically acceptable salt thereof, q is 1.

In some embodiments of formula (Jb), (Jd), (Je), or (Jf), each R^(b) isindependently selected from C₁₋₄alkyl, C₁₋₄alkoxyl, C₁₋₄haloalkyl, andC₁₋₄haloalkoxyl. In some embodiments, R^(b) is C₁₋₄haloalkyl. In someembodiments, R^(b) is independently selected from —CH₂F, —CHF₂, and—CF₃. In some embodiments, R^(b) is CF₃.

In some embodiments of formula (J), (Ja), (Jb), (Jc), (Jd), (Je), or(Jf), or a pharmaceutically acceptable salt thereof, R¹⁵ is selectedfrom H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, 4-10 memberedheterocyclyl, and C₆₋₁₀aryl. In some embodiments, R¹⁵ is selected fromH, C₁₋₆alkyl, and phenyl; and phenyl is optionally substituted with oneto three groups independently selected from halo, C₁₋₄alkyl,C₁₋₄alkoxyl, C₁₋₄haloalkyl, and C₁₋₄haloalkoxyl. In some embodiments,R¹⁵ is selected from H, methyl, ethyl, propyl, isopropyl, n-butyl,sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl,neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl, and phenyl. Insome embodiments, R¹⁵ is selected from H, methyl, ethyl, and phenyl. Insome embodiments, R¹⁵ is H. In some embodiments, R¹⁵ is methyl. In someembodiments, R¹⁵ is ethyl. In some embodiments, R¹⁵ is phenyl. In someembodiments, R¹⁵ is phenyl substituted with one group selected from F,—CH₃, —CF₃, —OCF₃, and —(CH₂)₂N(CH₂CH₃)₂. In some embodiments, R¹⁵ is—CH₂CH₂N(CH₂CH₃)₂.

In some embodiments of formula (J), (Ja), (Jb), (Jc), (Jd), (Je), or(Jf), or a pharmaceutically acceptable salt thereof, R¹⁵ is -L¹-R¹⁶. Insome embodiments, L¹ is selected from —CH₂—, —CH₂CH₂—, —CH(CH₃)—,—CH₂—O—C(O)—C₁₋₄alkyl, and —CH₂—O—C(O)—O—C₁₋₄alkyl. In some embodiments,R¹⁶ is selected from —CH₂CH₃, —CH(CH₃)₂, —C(CH₃)₃, —CH₂CH₂CH₃, phenyl,pyridinyl, imidazolyl, tetrahydrofuranyl, morpholinyl, andtetrahydropyranyl. Each phenyl, pyridinyl, imidazolyl,tetrahydrofuranyl, morpholinyl, and tetrahydropyranyl of R¹⁶ isoptionally substituted with one to two groups independently selectedfrom F, —CH₃, —CH₂CH₃, hydroxyl, and —COOH.

In some embodiments of formula (J), (Ja), (Jb), (Jc), (Jd), (Je), or(Jf), or a pharmaceutically acceptable salt thereof, R¹⁵ is selectedfrom H, —CH₃, —CH₂CH₃,

In some embodiments of formula (J), (Ja), (Jb), (Jc), (Jd), (Je), or(Jf), or a pharmaceutically acceptable salt thereof, R¹⁵ is selectedfrom H, —CH₃, and —CH₂CH₃. In some embodiments, R¹⁵ is H. In someembodiments, R¹⁵ is —CH₂CH₃.

In some embodiments of formula (Jg), or a pharmaceutically acceptablesalt thereof, Z¹ is O. In some embodiments, Z² is O. In someembodiments, Z³ is O. In some embodiments, Z⁴ is O. In some embodiments,Z¹ is NR^(z1). In some embodiments, Z² is NR^(z1). In some embodiments,Z³ is NR^(z1). In some embodiments, Z⁴ is NR^(z1). In some embodiments,R^(z1) is selected from H, —CH₃, and —CH₂CH₃. In some embodiments,R^(z1) is H.

In some embodiments of formula (Jg), or a pharmaceutically acceptablesalt thereof, R^(z) is —CH₃.

In some embodiments of formula (Jg), or a pharmaceutically acceptablesalt thereof, R³ and R⁵ are H.

In some embodiments of formula (Jg), or a pharmaceutically acceptablesalt thereof, each R² and R⁶ is independently selected from H, halo,C₁₋₄alkyl, C₁₋₄alkoxyl, C₁₋₄haloalkyl, C₁₋₄haloalkoxyl, C₃₋₆cycloalkyl,and 3-7 membered heterocyclyl. In some embodiments, each R² and R⁶ isindependently selected from F, Cl, —CH₃, —CD₃, —CH₂CH₃, —OCH₃, —OCH₂CH₃,—CH₂F, —CHF₂, —CF₃, —CH₂CH₂F, —CH₂CHF₂, —CH₂CF₃, —NH₂, and —N(CH₃)₂. Insome embodiments, each R² and R⁶ is independently selected from F, Cl,and —CH₃. In some embodiments, R² is F, and R⁶ is —CH₃. In someembodiments, each R² and R⁶ is independently selected from F, and Cl. Insome embodiments, R² and R⁶ are F.

In some embodiments of formula (Jg), or a pharmaceutically acceptablesalt thereof, R⁴ is

substituted with one to three R^(b). In some embodiments, each R^(b) isindependently selected from C₁₋₄alkyl, C₁₋₄alkoxyl, C₁₋₄haloalkyl, andC₁₋₄haloalkoxyl. In some embodiments, R^(b) is independently selectedfrom —CH₃, —CF₃, and —OCF₃. In some embodiments, R^(b) is —CF₃. In someembodiments, R⁴ is

In some embodiments of formula (Jg), or a pharmaceutically acceptablesalt thereof, R¹⁵ is selected from H, —CH₃, —CH₂CH₃, and —CH₂CH₂CH₃. Insome embodiments, R¹⁵ is H. In some embodiments, R¹⁵ is —CH₃. In someembodiments, R¹⁵ is —CH₂CH₃. In some embodiments, R¹⁵ is —CH₂CH₂CH₃.

In some embodiments, the compound of the present disclosure is selectedfrom:

In some embodiments, the compound of the present disclosure is selectedfrom:

Provided are also compounds described herein or pharmaceuticallyacceptable salts, isomer, or a mixture thereof, in which from 1 to nhydrogen atoms attached to a carbon atom may be replaced by a deuteriumatom or D, in which n is the number of hydrogen atoms in the molecule.As known in the art, the deuterium atom is a non-radioactive isotope ofthe hydrogen atom. Such compounds may increase resistance to metabolism,and thus may be useful for increasing the half-life of the compoundsdescribed herein or pharmaceutically acceptable salts, isomer, or amixture thereof when administered to a mammal. See, e.g., Foster,“Deuterium Isotope Effects in Studies of Drug Metabolism”, TrendsPharmacol. Sci., 5(12):524-527 (1984). Such compounds are synthesized bymeans well known in the art, for example by employing starting materialsin which one or more hydrogen atoms have been replaced by deuterium.

In some embodiments, the compound of the present disclosure contains oneto six deuterium (²H, or D). In some embodiments, one of R², R³, R⁴, R⁵,and R⁶ contains one to six D. In some embodiments, R⁶ contains one tosix D. In some embodiments, R⁶ is CD₃.

Provided are also pharmaceutically acceptable salts, hydrates, solvates,tautomeric forms, polymorphs, and prodrugs of the compounds describedherein. “Pharmaceutically acceptable” or “physiologically acceptable”refer to compounds, salts, compositions, dosage forms and othermaterials which are useful in preparing a pharmaceutical compositionthat is suitable for veterinary or human pharmaceutical use.“Pharmaceutically acceptable salts” or “physiologically acceptablesalts” include, for example, salts with inorganic acids and salts withan organic acid. In addition, if the compounds described herein areobtained as an acid addition salt, the free base can be obtained bybasifying a solution of the acid salt. Conversely, if the product is afree base, an addition salt, particularly a pharmaceutically acceptableaddition salt, may be produced by dissolving the free base in a suitableorganic solvent and treating the solution with an acid, in accordancewith conventional procedures for preparing acid addition salts from basecompounds. Those skilled in the art will recognize various syntheticmethodologies that may be used to prepare nontoxic pharmaceuticallyacceptable addition salts.

A “solvate” is formed by the interaction of a solvent and a compound.Solvates of salts of the compounds described herein are also provided.Hydrates of the compounds described herein are also provided.

A “prodrug” is a biologically inactive derivative of a drug that uponadministration to the human body is converted to the biologically activeparent drug according to some chemical or enzymatic pathway.

In certain embodiments, provided are optical isomers, racemates, orother mixtures thereof of the compounds described herein orpharmaceutically acceptable salts or a mixture thereof. In thosesituations, the single enantiomer or diastereomer, i.e., opticallyactive form, can be obtained by asymmetric synthesis or by resolution ofthe racemate. Resolution of racemates can be accomplished, for example,by conventional methods such as crystallization in the presence of aresolving agent, or chromatography, using, for example a chiral highpressure liquid chromatography (HPLC) column. In addition, provided arealso Z- and E-forms (or cis- and trans-forms) of the hydroxyamidinecompounds described herein. Specifically, Z- and E-forms are includedeven if only one designation is named for both carbon-carbon doublebonds as well as the hydroxyamidine bond.

Where chirality is not specified but is present, it is understood thatthe embodiment is directed to either the specific diastereomerically orenantiomerically enriched form; or a racemic or scalemic mixture of suchcompound(s).

“Enantiomers” are a pair of stereoisomers that are non-superimposablemirror images of each other. A 1:1 mixture of a pair of enantiomers is a“racemic” mixture. A mixture of enantiomers at a ratio other than 1:1 isa “scalemic” mixture.

“Diastereoisomers” are stereoisomers that have at least two asymmetricatoms, but which are not mirror-images of each other.

“Atropisomers” are stereoisomers arising due to hindered rotation abouta single bond, where the barrier to rotation about the bond is highenough to allow for isolation of individual stereoisomers.

In certain embodiments, provided are atropisomers thereof of thecompounds described herein or pharmaceutically acceptable salts.

Compositions provided herein that include a compound described herein orpharmaceutically acceptable salts, isomer, or a mixture thereof mayinclude racemic mixtures, or mixtures containing an enantiomeric excessof one enantiomer or single diastereomers or diastereomeric mixtures.All such isomeric forms of these compounds are expressly included hereinthe same as if each and every isomeric form were specifically andindividually listed.

In certain embodiments, provided are also chelates, non-covalentcomplexes, and mixtures thereof, of the compounds described herein orpharmaceutically acceptable salts, isomer, or a mixture thereof. A“chelate” is formed by the coordination of a compound to a metal ion attwo (or more) points. A “non-covalent complex” is formed by theinteraction of a compound and another molecule wherein a covalent bondis not formed between the compound and the molecule. For example,complexation can occur through van der Waals interactions, hydrogenbonding, and electrostatic interactions (also called ionic bonding).

Therapeutic Uses of the Compounds

The methods described herein may be applied to cell populations in vivoor ex vivo. “In vivo” means within a living individual, as within ananimal or human. In this context, the methods described herein may beused therapeutically in an individual. “Ex vivo” means outside of aliving individual. Examples of ex vivo cell populations include in vitrocell cultures and biological samples including fluid or tissue samplesobtained from individuals. Such samples may be obtained by methods wellknown in the art. Exemplary biological fluid samples include blood,cerebrospinal fluid, urine, and saliva. Exemplary tissue samples includetumors and biopsies thereof. In this context, the invention may be usedfor a variety of purposes, including therapeutic and experimentalpurposes. For example, the invention may be used ex vivo to determinethe optimal schedule and/or dosing of administration of an α4β7 integrininhibitor for a given indication, cell type, individual, and otherparameters. Information gleaned from such use may be used forexperimental purposes or in the clinic to set protocols for in vivotreatment. Other ex vivo uses for which the invention may be suited aredescribed below or will become apparent to those skilled in the art. Theselected compounds may be further characterized to examine the safety ortolerance dosage in human or non-human subjects. Such properties may beexamined using commonly known methods to those skilled in the art.

In some embodiments, compounds described herein, for example, compoundsof formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg),(IIh), or (IIi), or a pharmaceutically acceptable salt, stereoisomer,mixture of stereoisomers, tautomer, or deuterated analog thereof, may beused to treat subjects who have or are suspected of having diseasestates, disorders, and conditions (also collectively referred to as“indications”) responsive or believed to be responsive to the inhibitionof α4β7 integrin activity. In some embodiments, the compounds describedherein may be used to inhibit the activity of α4β7 integrin. In someembodiments, the compounds described herein may be used to inhibitexcessive or destructive immune reactions or growth or a proliferationof a cell, such as a cancer cell, or inhibit immunosuppression.

In some embodiments, compounds described herein, for example, compoundsof formula (J), (Ja), (Jb), (Jc), (Jd), (Je), or (Jf), or apharmaceutically acceptable salt, stereoisomer, mixture ofstereoisomers, tautomer, or deuterated analog thereof, may be used totreat subjects who have or are suspected of having disease states,disorders, and conditions (also collectively referred to as“indications”) responsive or believed to be responsive to the inhibitionof α4β7 integrin activity. In some embodiments, the compounds describedherein may be used to inhibit the activity of α4β7 integrin. In someembodiments, the compounds described herein may be used to inhibitexcessive or destructive immune reactions or growth or a proliferationof a cell, such as a cancer cell, or inhibit immunosuppression.

Methods

In some embodiments, the present disclosure provides a compounddescribed herein useful as an inhibitor of α4β7 integrin. In someembodiments, the present disclosure provides a method of treating aninflammatory disease or condition comprising administering a compounddescribed herein.

In some embodiments, the present disclosure provides a pharmaceuticalcomposition comprising a compound described herein and apharmaceutically acceptable carrier.

In some embodiments, the present disclosure provides a pharmaceuticalcomposition comprising a compound described herein and at least oneadditional therapeutic agent and at least one pharmaceuticallyacceptable excipient.

The present disclosure provides a compound described herein for use intherapy.

In another embodiment, the present disclosure provides a compounddescribed herein for use in the manufacture of a medicament for treatinga disease or condition provided herein.

In some embodiments, provided is a compound described herein useful forthe treatment of a disease or condition in a patient that is amenable totreatment by inhibiting α4β7 integrin. Diseases or conditions that maybe treated with the compounds described herein include a solid tumor,diabetes, an inflammatory disease, graft versus host disease, primarysclerosing cholangitis, HIV, an autoimmune disease, inflammatory boweldisease (IBD), alcoholic hepatitis, systemic lupus erythematosus (SLE),and lupus nephritis.

In some embodiments, provided is a compound described herein useful forthe treatment of an inflammatory disease or condition in a patient thatis mediated, at least in part, by α4β7 integrin.

“Administering” or “administration” refers to the delivery of one ormore therapeutic agents to a patient. In some embodiments, theadministration is a monotherapy wherein a compound described herein isthe only active ingredient administered to the patient in need oftherapy. In another embodiment, the administration is co-administrationsuch that two or more therapeutic agents are delivered together duringthe course of the treatment. In some embodiments, two or moretherapeutic agents may be co-formulated into a single dosage form or“combined dosage unit”, or formulated separately and subsequentlycombined into a combined dosage unit, as is typically for intravenousadministration or oral administration as a mono or bilayer tablet orcapsule.

In some embodiments, the compound described herein is administered to ahuman patient in need thereof in an effective amount, such as, fromabout 0.1 mg to about 1000 mg per dose of said compound. In someembodiments, the effective amount is from about 0.1 mg to about 400 mgper dose. In some embodiments, the effective amount is from about 0.1 mgto about 300 mg per dose. In some embodiments, the effective amount isfrom about 0.1 mg to about 200 mg per dose. In some embodiments, theeffective amount is from about 1 mg to about 100 mg per dose. In otherembodiments, the effective amount is about 1 mg, about 3 mg, about 5 mg,about 10 mg, about 15 mg, about 18 mg, about 20 mg, about 30 mg, about40 mg, about 60 mg, about 80 mg, about 100 mg, about 200 mg, or about300 mg per dose.

In some embodiments, the compound described herein and at least oneadditional therapeutic agent is administered to a human patient in needthereof in an effective amount of each agent, independently from about0.1 mg to about 1000 mg per dose of a compound or formulation per doseper compound. In some embodiments, the effective amount of thecombination treatment of a compound described herein and an additionalcompound is independently from about 0.1 mg to about 200 mg per compoundper dose. In some embodiments, the effective amount of the combinationtreatment of a compound described herein and an additional compound isindependently from about 1 mg to about 100 mg per compound per dose. Inother embodiments, the effective amount of the combination treatment ofa compound described herein and an additional compound is for eachcomponent, about 1 mg, about 3 mg, about 5 mg, about 10 mg, about 15 mg,about 18 mg, about 20 mg, about 30 mg, about 40 mg, about 60 mg, about80 mg, about 100 mg, about 200 mg, or about 500 mg each per dose.

In some embodiments, the dose of a compound described herein and/or acombination of the dose of the compound described herein and/or the doseof an additional therapeutic agent is administered once per day, twiceper day, or thrice per day. In yet another embodiment, the dose of acompound described herein and/or the dose of an additional therapeuticagent is administered as a loading dose of from about 0.1 mg to about1000 mg per compound on the first day and each day or on alternate daysor weekly for up to a month followed by a regular regimen of a compounddescribed herein and/or one or more additional therapeutic agents ortherapies. The maintenance dose may be about 0.1 mg to about 1000 mgonce per day, twice per day, thrice per day, or weekly, for eachcomponent of a multi component drug regimen. A qualified care giver ortreating physician is aware of what dose regimen is best for aparticular patient or particular presenting conditions and will makeappropriate treating regimen decisions for that patient. Thus, inanother embodiment, the qualified caregiver is able to tailor a doseregimen of the compound described herein and/or an additionaltherapeutic agent(s) as disclosed herein to fit with the particularneeds of the patient. Thus, it will be understood that the amount of thedose of a compound described herein and the amount of the dose of anadditional therapeutic agent actually administered will usually bedetermined by a physician, in light of the relevant circumstances,including the condition(s) to be treated, the chosen route ofadministration, the actual compound (e.g., salt or free base)administered and its relative activity, the age, weight, and response ofthe individual patient, the severity of the patient's symptoms, and thelike.

Co-administration may also include administering component drugs e.g.,one on more compounds described herein and one or more additional (e.g.,a second, third, fourth or fifth) therapeutic agent(s). Such combinationof one on more compounds described herein and one or more additionaltherapeutic agent(s) may be administered simultaneously or in sequence(one after the other) within a reasonable period of time of eachadministration (e.g., about 1 minute to 24 hours) depending on thepharmacokinetic and/or pharmacodynamics properties of each agent or thecombination. Co-administration may also involve treatment with a fixedcombination wherein agents of the treatment regimen are combinable in afixed dosage or combined dosage medium e.g., solid, liquid or aerosol.In some embodiments, a kit may be used to administer the drug or drugcomponents.

Thus, some embodiments of the present disclosure is a method of treatinga disease or condition mediated, at least in part, by α4β7 integrin,comprising administering therapeutically effective amounts offormulations of one on more compounds described herein and one or moreadditional therapeutic agents, including for example, via a kit to apatient in need thereof. It will be understood that a qualified caregiver will administer or direct the administration of a therapeuticallyeffective amount of any of the compound(s) or combinations of compoundsof the present disclosure.

“Intravenous administration” is the administration of substancesdirectly into a vein, or “intravenously.” Compared with other routes ofadministration, the intravenous (IV) route is a faster way to deliverfluids and medications throughout the body. An infusion pump can allowprecise control over the flow rate and total amount of medicationdelivered. However, in cases where a change in the flow rate would nothave serious consequences, or if pumps are not available, the drip isoften left to flow simply by placing the bag above the level of thepatient and using the clamp to regulate the rate. Alternatively, a rapidinfuser can be used if the patient requires a high flow rate and the IVaccess device is of a large enough diameter to accommodate it. This iseither an inflatable cuff placed around the fluid bag to force the fluidinto the patient or a similar electrical device that may also heat thefluid being infused. When a patient requires medications only at certaintimes, intermittent infusion is used which does not require additionalfluid. It can use the same techniques as an intravenous drip (pump orgravity drip), but after the complete dose of medication has been given,the tubing is disconnected from the IV access device. Some medicationsare also given by IV push or bolus, meaning that a syringe is connectedto the IV access device and the medication is injected directly (slowly,if it might irritate the vein or cause a too-rapid effect). Once amedicine has been injected into the fluid stream of the IV tubing theremust be some means of ensuring that it gets from the tubing to thepatient. Usually this is accomplished by allowing the fluid stream toflow normally and thereby carry the medicine into the bloodstream;however, a second fluid injection is sometimes used, as a “flush”,following the injection to push the medicine into the bloodstream morequickly. Thus, in some embodiments, compound(s) or combination ofcompounds described herein may be administered by IV administrationalone or in combination with administration of certain components of thetreatment regimen by oral or parenteral routes.

“Oral administration” is a route of administration where a substance istaken through the mouth, and includes buccal, sub labial, and sublingualadministration, as well as enteral administration and that through therespiratory tract, unless made through e.g., tubing so the medication isnot in direct contact with any of the oral mucosa. Typical form for theoral administration of therapeutic agents includes the use of tablets orcapsules. Thus, in some embodiments, compound(s) or combination ofcompounds described herein may be administered by oral route alone or incombination with administration of certain components of the treatmentregimen by IV or parenteral routes.

Pharmaceutical Formulations

The compounds described herein may be administered in a pharmaceuticalformulation. Pharmaceutical formulations/compositions contemplated bythe present disclosure comprise, in addition to a carrier, the compounddescribed herein or a combination of compounds described hereinoptionally in combination with an additional therapeutic agent.

Pharmaceutical formulations/compositions contemplated by the presentdisclosure may also be intended for administration by injection andinclude aqueous solutions, oil suspensions, emulsions (with sesame oil,corn oil, cottonseed oil, or peanut oil) as well as elixirs, mannitol,dextrose, or a sterile aqueous solution, and similar pharmaceuticalvehicles. Aqueous solutions in saline are also conventionally used forinjection. Ethanol, glycerol, propylene glycol, liquid polyethyleneglycol, and the like (and suitable mixtures thereof), cyclodextrinderivatives, and vegetable oils may also be employed. The properfluidity can be maintained, for example, by the use of a coating, suchas lecithin, by the maintenance of the required particle size in thecase of dispersion and/or by the use of surfactants. The prevention ofthe action of microorganisms can be brought about by variousantibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

Sterile injectable solutions are prepared by incorporating the componentcompound(s) in the required amount in the appropriate solvent withvarious other ingredients as enumerated above or as required, followedby filtered sterilization. Generally, dispersions are prepared byincorporating the various sterilized active ingredients into a sterilevehicle which contains the basic dispersion medium and the requiredother ingredients from those enumerated above. In the case of sterilepowders for the preparation of sterile injectable solutions, thepreferred methods of preparation are vacuum-drying and freeze-dryingtechniques which yield a powder of the active ingredient(s) plus anyadditional desired ingredient from a previously sterile-filteredsolution thereof.

In making pharmaceutical compositions that comprise compound describedherein optionally in combination with an additional agent/therapy usefulfor the purpose or pharmaceutically acceptable salt thereof, the activeingredient is usually diluted by an excipient or carrier and/or enclosedor mixed with such a carrier that may be in the form of a capsule,sachet, paper or other container. When the excipient serves as adiluent, it can be a solid, semi-solid, or liquid material (as above),which acts as a vehicle, carrier or medium for the active ingredient.Thus, the compositions can be in the form of tablets, pills, powders,lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions,syrups, aerosols (as a solid or in a liquid medium), ointmentscontaining, for example, up to 20% by weight of the active compounds,soft and hard gelatin capsules, sterile injectable solutions, andsterile packaged powders.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The formulations can additionally include: lubricating agentssuch as talc, magnesium stearate, and mineral oil; wetting agents;emulsifying and suspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents.

The compositions of the disclosure may be formulated so as to providequick, sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.In some embodiments, sustained release formulations are used. Controlledrelease drug delivery systems for oral administration include osmoticpump systems and dissolutional systems containing polymer-coatedreservoirs or drug-polymer matrix formulations.

Certain compositions are preferably formulated in a unit dosage form.The term “unit dosage forms” or “combined dosage unit” refers tophysically discrete units suitable as unitary dosages for human subjectsand other mammals, each unit containing a predetermined quantity of oneor more of the active materials (e.g., a compound described herein,optionally in combination with an additional therapeutic agentcalculated to produce the desired effect, in association with a suitablepharmaceutical excipient in for example, a tablet, capsule, ampoule orvial for injection. It will be understood, however, that the amount ofeach active agent actually administered will be determined by aphysician, in the light of the relevant circumstances, including thecondition to be treated, the chosen route of administration, the actualcompounds administered and their relative activity, the age, weight, andresponse of the individual patient, the severity of the patient'ssymptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient(s) is/are mixed with a pharmaceutical excipient to form asolid pre-formulation composition containing a homogeneous mixture of acompound of the present disclosure. When referring to thesepre-formulation compositions as homogeneous, it is meant that the activeingredient(s) are dispersed evenly throughout the composition so thatthe composition may be readily subdivided into equally effective unitdosage forms such as tablets, pills and capsules.

The tablets or pills comprising compound described herein of the presentdisclosure optionally in combination with the second agent may be coatedor otherwise compounded to provide a dosage form affording the advantageof prolonged action, or to protect from the acidic conditions of thestomach. For example, the tablet or pill can comprise an inner dosageand an outer dosage element, the latter being in the form of an envelopeover the former. In some embodiments, the inner dosage element maycomprise the compound described herein and the outer dosage element maycomprise the second or additional therapeutic agent or vice versa.Alternatively, the combined dosage unit may be side by sideconfiguration as in a capsule or tablet where one portion or half of thetablet or capsule is filled with a formulation of the compound describedherein while the other portion or half of the table or capsule comprisesthe additional therapeutic agent.

A variety of materials may be used for such enteric layers or coatings,such materials including a number of polymeric acids and mixtures ofpolymeric acids with such materials as shellac, cetyl alcohol, andcellulose acetate. One of ordinary skill in the art is aware oftechniques and materials used in the manufacture of dosages offormulations disclosed herein.

A “sustained release formulation” or “extended release formulation” is aformulation which is designed to slowly release a therapeutic agent intothe body over an extended period of time, whereas an “immediate releaseformulation” is a formulation which is designed to quickly release atherapeutic agent into the body over a shortened period of time. In somecases, the immediate release formulation may be coated such that thetherapeutic agent is only released once it reaches the desired target inthe body (e.g., the stomach). One of ordinary skill in the art is ableto develop sustained release formulations of the presently disclosedcompounds without undue experimentation. Thus, in some embodiments,compound(s) or combination of compounds described herein may bedelivered via sustained released formulations alone or in combinationwith administration of certain components of the treatment regimen byoral, IV or parenteral routes.

A lyophilized formulation may also be used to administer a compounddescribed herein singly or in combination with an additional therapeuticagent. One of skill in the art is aware of how to make and uselyophilized formulations of drug substances amenable to lyophilization.

Spray-dried formulation may also be used to administer a compounddescribed herein singly or in combination with an additional therapeuticagent. One of skill in the art is aware of how to make and usespray-dried formulations of drug substances amenable to spray-drying.Other known formulation techniques may also be employed to formulate acompound or combination of compounds disclosed herein.

The compounds disclosed herein are useful for the treatment of diseasesor conditions mediated, at least in part, by α4β7 integrin. Non-limitingexamples of diseases or conditions mediated, at least in part, by α4β7integrin include, without limitation, acne, acid-induced lung injury,Addison's disease, adrenal hyperplasia, adrenocortical insufficiency,adult-onset Still's disease, adult respiratory distress syndrome (ARDS),age-related macular degeneration, aging, alcoholic hepatitis, alcoholicliver disease, allergen-induced asthma, allergic bronchopulmonary,allergic conjunctivitis, allergic contact dermatitis, allergies,allergic encephalomyelitis, allergic neuritis, allograft rejection,alopecia, alopecia areata, Alzheimer's disease, amyloidosis, amyotrophiclateral sclerosis, angina pectoris, angioedema, angiofibroma, anhidroticectodermal dysplasia-ill, anti-glomerular basement membrane disease,antigen-antibody complex mediated diseases, ankylosing spondylitis,antiphospholipid syndrome, aphthous stomatitis, appendicitis, arthritis,ascites, aspergillosis, asthma, atherosclerosis, atheroscleroticplaques, atopic dermatitis, atrophic thyroiditis, autoimmune diseases,autoimmune hemolytic anemia (immune pancytopenia, paroxysmal nocturnalhemoglobinuria), autoimmune polyendocrinopathies, autoimmunethrombocytopenia (idiopathic thrombocytopenic purpura, immune-mediatedthrombocytopenia), autoimmune hepatitis, autoimmune thyroid disorders,autoinflammatory diseases, back pain, Bacillus anthracis infection,Bechet's disease, bee sting-induced inflammation, Behçet's syndrome,Bell's palsy, berylliosis, Blau syndrome, bone pain, bronchiolitis,bullous pemphigoid (BP) asthma, burns, bursitis, cardiac hypertrophy,carpal tunnel syndrome, Castleman's disease, catabolic disorders,cataracts, Celiac disease, cerebral aneurysm, chemical irritant-inducedinflammation, chorioretinitis, chronic atypical neutrophilic dermatosiswith lipodystrophy and elevated temperature (CANDLE) syndrome, chronicheart failure, chronic lung disease of prematurity, chronic obstructivepulmonary disease (COPD), chronic pancreatitis, chronic prostatitis,chronic recurrent multifocal osteomyelitis, cicatricial alopecia,colitis, complex regional pain syndrome, complications of organtransplantation, conjunctivitis, connective tissue disease, contactdermatitis, corneal graft neovascularization, corneal ulcer, Crohn'sdisease, cryopyrin-associated periodic syndromes, cutaneous lupuserythematosus (CLE), cryptococcosis, cystic fibrosis, deficiency of theinterleukin-1 receptor antagonist (DIRA), dermatitis, dermatitisendotoxemia, dermatomyositis, diabetic macular edema, diverticulitis,eczema, encephalitis, endometriosis, endotoxemia, eosinophilicpneumonias, epicondylitis, epidermolysis bullosa, erythema multiforme,erythroblastopenia, esophagitis, familial amyloidotic polyneuropathy,familial cold urticarial, familial Mediterranean fever, fetal growthretardation, fibromyalgia, fistulizing Crohn's disease, food allergies,giant cell arteritis, glaucoma, glioblastoma, glomerular disease,glomerular nephritis, glomerulonephritis, gluten-sensitive enteropathy,gout, gouty arthritis, graft-versus-host disease (GVHD), granulomatoushepatitis, Graves' disease, growth plate injuries, Guillain-Barresyndrome, gut diseases, hair loss, Hashimoto's thyroiditis, head injury,headache, hearing loss, heart disease, hemangioma, hemolytic anemia,hemophilic joints, Henoch-Scholein purpura, hepatitis, hereditaryperiodic fever syndrome, heritable disorders of connective tissue,herpes zoster and simplex, hidradenitis suppurativa (HS), hipreplacement, Hodgkin's disease, Huntington's disease, hyaline membranedisease, hyperactive inflammatory response, hyperammonemia,hypercalcemia, hypercholesterolemia, hypereosinophilic syndrome (HES),hyperimmunoglobulinemia D with recurrent fever (HIDS), hypersensitivitypneumonitis, hypertropic bone formation, hypoplastic and other anemias,hypoplastic anemia, ichthyosis, idiopathic demyelinating polyneuropathy,Idiopathic inflammatory myopathies (dermatomyositis, polymyositis),idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpura,immunoglobulin nephropathies, immune complex nephritis, immunethrombocytopenic purpura (ITP), incontinentia pigmenti (IP,Bloch-Siemens syndrome), infectious mononucleosis, infectious diseasesincluding viral diseases such as AIDS (HIV infection), hepatitis A, B,C, D, and E, herpes; inflammation, inflammation of the CNS, inflammatorybowel disease (IBD), inflammatory disease of the lower respiratory tractincluding bronchitis or chronic obstructive pulmonary diseases,inflammatory disease of the upper respiratory tract including the noseand sinuses such as rhinitis or sinusitis, inflammatory diseases of therespiratory tract, inflammatory ischemic event such as stroke or cardiacarrest, inflammatory lung disease, inflammatory myopathy such asmyocarditis, inflammatory liver disease, inflammatory neuropathy,inflammatory pain, insect bite-induced inflammation, interstitialcystitis, interstitial lung disease, iritis, irritant-inducedinflammation, ischemia/reperfusion, joint replacement, juvenilearthritis, juvenile rheumatoid arthritis, keratitis, kidney injurycaused by parasitic infections, kidney transplant rejection,leptospirosis, leukocyte adhesion deficiency, lichen sclerosus (LS),Lambert-Eaton myasthenic syndrome, Loeffler's syndrome, lupus, lupusnephritis, Lyme disease, Marfan syndrome (MFS), mast cell activationsyndrome, mastocytosis, meningitis, meningioma, mesothelioma, mixedconnective tissue disease, Muckle-Wells syndrome (urticaria deafnessamyloidosis), mucositis, multiple organ injury syndrome, multiplesclerosis, muscle wasting, muscular dystrophy, myasthenia gravis (MG),myelodysplastic syndrome, myocarditis, myositis, nasal sinusitis,necrotizing enterocolitis, neonatal onset multisystem inflammatorydisease (NOMID), neovascular glaucoma, nephrotic syndrome, neuritis,neuropathological diseases, non-allergen induced asthma, obesity, ocularallergy, optic neuritis, organ transplant rejection, Osier-Webersyndrome, osteoarthritis, osteogenesis imperfecta, osteonecrosis,osteoporosis, osterarthritis, otitis, pachyonychia congenita, Paget'sdisease, Paget's disease of bone, pancreatitis, Parkinson's disease,pediatric rheumatology, pelvic inflammatory disease, pemphigus,pemphigus vulgaris (PV), bullous pemphigoid (BP), pericarditis, periodicfever, periodontitis, peritoneal endometriosis, pernicious anemia(Addison's disease), pertussis, PFAPA (periodic fever aphthouspharyngitis and cervical adenopathy), pharyngitis and adenitis (PFAPAsyndrome), plant irritant-induced inflammation, pneumocystis infection,pneumonia, pneumonitis, poison ivy/urushiol oil-induced inflammation,polyarthritis nodosa, polychondritis, polycystic kidney disease,polymyalgia rheumatic, giant cell arteritis, polymyositis, pouchitis,reperfusion injury and transplant rejection, primary biliary cirrhosis,primary pulmonary hypertension, primary sclerosing cholangitis (PSC),proctitis, psoriasis, psoriasis vulgaris, psoriatic arthritis, psoriaticepidermis, psychosocial stress diseases, pulmonary disease, pulmonaryfibrosis, pulmonary hypertension, pyoderma gangrenosum, pyogenicgranuloma retrolental fibroplasias, pyogenic sterile arthritis,Raynaud's syndrome, Reiter's disease, reactive arthritis, renal disease,renal graft rejection, reperfusion injury, respiratory distresssyndrome, retinal disease, retrolental fibroplasia, Reynaud's syndrome,rheumatic carditis, rheumatic diseases, rheumatic fever, rheumatoidarthritis, rhinitis, rhinitis psoriasis, rosacea, sarcoidosis,Schnitzler syndrome, scleritis, sclerosis, scleroderma, scoliosis,seborrhea, sepsis, septic shock, severe pain, Sezary syndrome, sicklecell anemia, silica-induced disease (Silicosis), Sjogren's syndrome,skin diseases, skin irritation, skin rash, skin sensitization (contactdermatitis or allergic contact dermatitis), sleep apnea, spinal cordinjury, spinal stenosis, spondyloarthropathies, sports injuries, sprainsand strains, Stevens-Johnson syndrome (SJS), stroke, subarachnoidhemorrhage, sunburn, synovial inflammation, systemic inflammatoryresponse syndrome (SIRS), systemic lupus erythematosus, systemic mastcell disease (SMCD), systemic vasculitis, systemic-onset juvenileidiopathic arthritis, temporal arteritis, tendinitis, tenosynovitis,thrombocytopenia, thyroditis, thyroiditis, tissue transplant,toxoplasmosis, trachoma, transplantation rejection, traumatic braininjury, tuberculosis, tubulointerstitial nephritis, tumor necrosisfactor (TNF) receptor associated periodic syndrome (TRAPS), type 1diabetes, type 2 diabetes, complications from type 1 or type 2 diabetes,ulcerative colitis, urticaria, uterine fibroids, uveitis, uveoretinitis,vascular restenosis, vasculitis, vasculitis (NHLBI), vitiligo, Wegener'sgranulomatosis, and Whipple's disease.

In further embodiments, the methods are provided for alleviating asymptom of a disease or disorder mediated, at least in part, by α4β7integrin. In some embodiments, the methods include identifying a mammalhaving a symptom of a disease or disorder mediated, at least in part, byα4β7 integrin, and providing to the mammal an amount of a compound asdescribed herein effective to ameliorate (i.e., lessen the severity of)the symptom.

In some embodiments, the disease or condition mediated, at least inpart, by α4β7 integrin is an inflammatory disease or LPS inducedendotoxin shock. In some embodiments, the disease is an autoimmunedisease. In particular embodiments, the autoimmune disease is systemiclupus erythematosus (SLE), myestenia gravis, rheumatoid arthritis (RA),acute disseminated encephalomyelitis, idiopathic thrombocytopenicpurpura, multiple sclerosis (MS), inflammatory bowel disease (IBD),sepsis, psoriasis, Sjoegren's syndrome, autoimmune hemolytic anemia,asthma, or chronic obstructive pulmonary disease (COPD), ankylosingspondylitis, acute gout and ankylosing spondylitis, reactive arthritis,monoarticular arthritis, osteoarthritis, gouty arthritis, juvenilearthritis, juvenile onset rheumatoid arthritis, juvenile rheumatoidarthritis or psoriatic arthritis. In other embodiments, the disease isinflammation. In yet other embodiments, the disease is excessive ordestructive immune reactions, such as asthma, rheumatoid arthritis,multiple sclerosis, chronic obstructive pulmonary disease (COPD), andlupus.

In some embodiments, the disease or condition mediated, at least inpart, by α4β7 integrin is inflammatory bowel disease (IBD). The term“inflammatory bowel disease” or “IBD” as used herein is a collectiveterm describing inflammatory disorders of the gastrointestinal tract,the most common forms of which are ulcerative colitis and Crohn'sdisease. Other forms of IBD that can be treated with the presentlydisclosed compounds, compositions and methods include diversion colitis,ischemic colitis, infectious colitis, chemical colitis, microscopiccolitis (including collagenous colitis and lymphocytic colitis),atypical colitis, pseudomembranous colitis, fulminant colitis, autisticenterocolitis, indeterminate colitis, Behçet's disease, gastroduodenalCD, jejunoileitis, ileitis, ileocolitis, Crohn's (granulomatous)colitis, irritable bowel syndrome, mucositis, radiation inducedenteritis, short bowel syndrome, celiac disease, stomach ulcers,diverticulitis, pouchitis, proctitis, and chronic diarrhea.

Treating or preventing IBD also includes ameliorating or reducing one ormore symptoms of IBD. As used herein, the term “symptoms of IBD” refersto detected symptoms such as abdominal pain, diarrhea, rectal bleeding,weight loss, fever, loss of appetite, and other more seriouscomplications, such as dehydration, anemia and malnutrition. A number ofsuch symptoms are subject to quantitative analysis (e.g. weight loss,fever, anemia, etc.). Some symptoms are readily determined from a bloodtest (e.g. anemia) or a test that detects the presence of blood (e.g.rectal bleeding). The term “wherein said symptoms are reduced” refers toa qualitative or quantitative reduction in detectable symptoms,including but not limited to a detectable impact on the rate of recoveryfrom disease (e.g. rate of weight gain). The diagnosis is typicallydetermined by way of an endoscopic observation of the mucosa, andpathologic examination of endoscopic biopsy specimens.

The course of IBD varies, and is often associated with intermittentperiods of disease remission and disease exacerbation. Various methodshave been described for characterizing disease activity and severity ofIBD as well as response to treatment in subjects having IBD. Treatmentaccording to the present methods is generally applicable to a subjecthaving IBD of any level or degree of disease activity.

In some embodiments, the disease or condition treated by theadministration of a compound of composition described herein includesacute gout and ankylosing spondylitis, allergic disorders, Alzheimer'sdisease, Amyotrophic lateral sclerosis (ALS), Amyotrophic lateralsclerosis and multiple sclerosis, atherosclerosis, bacterial infections,bone cancer pain and pain due to endometriosis, BRAF resistant melanoma,brain stem glioma or pituitary adenomas, burns, bursitis, cancer of theanal region, cancer of the endocrine system, cancer of the kidney orureter (e.g. renal cell carcinoma, and carcinoma of the renal pelvis),cancer of the penis, cancer of the small intestine, cancer of thethyroid, cancer of the urethra, cancers of the blood such as acutemyeloid leukemia, cancers of the tongue, carcinoma of the cervix,carcinoma of the endometrium, carcinoma of the fallopian tubes,carcinoma of the renal pelvis, carcinoma of the vagina or carcinoma ofthe vulva, chronic myeloid leukemia, chronic or acute leukemia, chronicpain, classic Bartter syndrome, common cold conjunctivitis, coronaryheart disease, cutaneous or intraocular melanoma, dermatitis,dysmenorrhea, eczema, endometriosis, familial adenomatous polyposis,fibromyalgia, fungal infections, gout, gynecologic tumors, uterinesarcomas, carcinoma of the fallopian tubes, headache, hemophilicarthropathy, Parkinson's disease, AIDS, herpes zoster, Hodgkin'sdisease, Huntington's, hyperprostaglandin E syndrome, influenza, iritis,juvenile arthritis, juvenile onset rheumatoid arthritis, juvenilerheumatoid arthritis, low back and neck pain, lymphocytic lymphomas,myofascial disorders, myositis, neuralgia, neurodegenerative disorderssuch as Alzheimer's disease, neuroinflammatory disorders, neuropathicpain, carcinoma of the vulva, Parkinson's disease, pediatric malignancy,pulmonary fibrosis rectal cancer, rhinitis, sarcoidosis, sarcomas ofsoft tissues, scleritis, skin cancer, solid tumors of childhood, spinalaxis tumors, sprains and strains, stomach cancer, stroke, subacute andchronic musculoskeletal pain syndromes such as bursitis, surgical ordental procedures, symptoms associated with influenza or other viralinfections, synovitis, toothache, ulcers, uterine cancer, uterinesarcomas, uveitis, vasculitis, viral infections, viral infections {e.g.influenza) and wound healing.

Criteria useful for assessment of disease activity in subjects withulcerative colitis can be found in, e.g., Truelove et al. (1955) Br MedJ 2:1041-1048.) Using these criteria, disease activity can becharacterized in a subject having IBD as mild disease activity or severedisease activity. Subjects who do not meet all the criteria for severedisease activity, and who exceed the criteria for mild disease activityare classified as having moderate disease activity.

The presently disclosed treatment methods can also be applied at anypoint in the course of the disease. In some embodiments, the methods areapplied to a subject having IBD during a time period of remission (i.e.,inactive disease). In such embodiments, the present methods providebenefit by extending the time period of remission (e.g., extending theperiod of inactive disease) or by preventing, reducing, or delaying theonset of active disease. In other embodiments, methods may be applied toa subject having IBD during a period of active disease. Such methodsprovide benefit by reducing the duration of the period of activedisease, reducing or ameliorating one or more symptoms of IBD, ortreating IBD.

Measures for determining efficacy of treatment of IBD in clinicalpractice have been described and include, for example, the following:symptom control; fistula closure; extent of corticosteroid therapyrequired; and, improvement in quality of life. Heath-related quality oflife (HRQL) can be assessed using the Inflammatory Bowel DiseaseQuestionnaire (IBDQ), which is extensively used in clinical practice toassess quality of life in a subject with IBD. (See Guyatt et al. (1989)Gastroenterology 96:804-810.) In some embodiments, the disease orcondition is immune-mediated liver injury, disease or condition.

In some embodiments, the disease or condition mediated, at least inpart, by α4β7 integrin is alcoholic hepatitis. Alcoholic hepatitis is aclinical syndrome characterized by jaundice and liver failure thatdevelops in subjects with chronic and active alcohol abuse. (SeeAkriviadis E. et. al, Ann Gastroenterol. 2016 April-June; 29(2):236-237). Alcoholic hepatitis can cause cirrhosis and fibrosis of theliver cells. Glucocorticoids, (e.g. prednisolone) and phosphodiesteraseinhibitors (e.g. pentoxifylline) can be used to treat alcoholichepatitis. The compounds herein can be used as stand-alone treatments orin combination with the current treatments for alcoholic hepatitis.

In one aspect, the present disclosure provides methods of treating orpreventing a human immunodeficiency virus (HIV) infection in a subjectin need thereof, comprising administering to the subject atherapeutically effective amount of a compound provided herein, or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition provided herein.

In some embodiments, the disease or condition mediated, at least inpart, by α4β7 integrin is systemic lupus erythematosus (SLE), lupusnephritis, lupus-related, or other autoimmune disorders or a symptom ofSLE. Symptoms of systemic lupus erythematosus include joint pain, jointswelling, arthritis, fatigue, hair loss, mouth sores, swollen lymphnodes, sensitivity to sunlight, skin rash, headaches, numbness,tingling, seizures, vision problems, personality changes, abdominalpain, nausea, vomiting, abnormal heart rhythms, coughing up blood anddifficulty breathing, patchy skin color and Raynaud's phenomenon.

Combination Therapy

Also provided are methods of treatment in which a compound describedherein is given to a patient in combination with one or more additionalactive agents or therapy.

Thus in some embodiments, a method of treating diseases or conditionsmediated, at least in part, by α4β7 integrin and/or diseases or symptomsthat co-present or are exacerbated or triggered by the diseases orconditions mediated, at least in part, by α4β7 integrin, e.g., anallergic disorder and/or an autoimmune and/or inflammatory disease,and/or an acute inflammatory reaction, comprises administering to apatient in need thereof an effective amount of a compound describedherein optionally in combination with an additional agent (e.g., asecond, third, fourth or fifth active agent) which can be useful fortreating diseases or conditions mediated, at least in part, by α4β7, anallergic disorder and/or an autoimmune and/or inflammatory disease,and/or an acute inflammatory reaction incident to or co-presenting withdiseases or conditions mediated, at least in part, by α4β7 integrin.Treatment with the second, third, fourth or fifth active agent may beprior to, concomitant with, or following treatment with a compounddescribed herein. In some embodiments, a compound described herein iscombined with another active agent in a single dosage form. Suitabletherapeutics that may be used in combination with a compound describedherein include, but are not limited to, therapeutic agents providedherein, or a combination comprising at least one therapeutic agentprovided herein.

Included herein are methods of treatment in which a compound describedherein is administered in combination with an agent for treatment of aninflammatory disease or condition. Examples of agents for treatment ofan inflammatory disease or condition that can be used in combinationwith compounds described herein, include alpha-fetoprotein modulators;adenosine A3 receptor antagonist; adrenomedullin ligands; AKT1 geneinhibitors; antibiotics; antifungals; ASK1 inhibitors; ATPaseinhibitors; beta adrenoceptor antagonists; BTK inhibitors; calcineurininhibitors; carbohydrate metabolism modulators; cathepsin S inhibitors;CCR9 chemokine antagonists; CD233 modulators; CD29 modulators; CD3antagonists; CD40 ligand inhibitors; CD40 ligand receptor antagonists;chemokine CXC ligand inhibitors; CHST15 gene inhibitors; collagenmodulators; CSF-1 antagonists; CX3CR1 chemokine modulators; ecobiotics;eotaxin ligand inhibitors; EP4 prostanoid receptor agonists; F1F0 ATPsynthase modulators; farnesoid X receptor (FXR and NR1H4) agonists ormodulators; fecal microbiota transplantation (FMT); fractalkine ligandinhibitors; free fatty acid receptor 2 antagonists; GATA 3 transcriptionfactor inhibitors; glucagon-like peptide 2 agonists; glucocorticoidagonists; Glucocorticoid receptor modulators; guanylate cyclase receptoragonists; HIF prolyl hydroxylase inhibitors; histone deacetylaseinhibitors; HLA class II antigen modulators; hypoxia inducible factor-1stimulator; ICAM1 gene inhibitors; IL-1 beta ligand modulators; IL-12antagonists; IL-13 antagonists; IL-18 antagonists; IL-22 agonists; IL-23antagonists; IL-23A inhibitors; IL-6 antagonists; IL-7 receptorantagonists; IL-8 receptor antagonists; integrin alpha-4/beta-1antagonists; integrin alpha-4/beta-7 antagonists; integrin antagonists;interleukin ligand inhibitors; interleukin receptor 17A antagonists;interleukin-1 beta ligands; interleukin 1 like receptor 2 inhibitors;IL-6 receptor modulators; JAK tyrosine kinase inhibitors; Jak1 tyrosinekinase inhibitors; Jak3 tyrosine kinase inhibitors; lactoferrinstimulators; LanC like protein 2 modulators; leukocyte elastateinhibitors; leukocyte proteinase-3 inhibitors; MAdCAM inhibitors;melanin concentrating hormone (MCH-1) antagonist; melanocortin agonists;metalloprotease-9 inhibitors; microbiome-targeting therapeutics;natriuretic peptide receptor C agonists; neuregulin-4 ligands; NLPR3inhibitors; NKG2 D activating NK receptor antagonists; nuclear factorkappa B inhibitors; opioid receptor antagonists; OX40 ligand inhibitors;oxidoreductase inhibitors; P2X7 purinoceptor modulators; PDE 4inhibitors; Pellino homolog 1 inhibitors; PPAR alpha/delta agonists;PPAR gamma agonists; protein fimH inhibitors; P-selectin glycoproteinligand-1 inhibitors; Ret tyrosine kinase receptor inhibitors; RIP-1kinase inhibitors; RIP-2 kinase inhibitors; RNA polymerase inhibitors;sphingosine 1 phosphate phosphatase 1 stimulators;sphingosine-1-phosphate receptor-1 agonists; sphingosine-1-phosphatereceptor-5 agonists; sphingosine-1-phosphate receptor-1 antagonists;sphingosine-1-phosphate receptor-1 modulators; stem cell antigen-1inhibitors; superoxide dismutase modulators; SYK inhibitors; tissuetransglutaminase inhibitor; TLR-3 antagonists; TLR-4 antagonists;Toll-like receptor 8 (TLR8) inhibitors; TLR-9 agonists; TNF alpha ligandinhibitors; TNF ligand inhibitors; TNF alpha ligand modulators; TNFantagonists; TPL-2 inhibitors; tumor necrosis factor 14 ligandmodulators; tumor necrosis factor 15 ligand inhibitors; Tyk2 tyrosinekinase inhibitors; type I IL-1 receptor antagonists; vanilloid VR1agonists; and zonulin inhibitors, and combinations thereof.

Adenosine A3 receptor antagonists include PBF-677.

Adrenomedullin ligands include adrenomedullin.

Antibiotics include ciprofloxacin, clarithromycin, metronidazole,vancomycin, rifamycin, rifaximin, and tosufloxacin.

ASK1 inhibitors include GS-4997.

Alpha-fetoprotein modulators include ACT-101.

Anti-CD28 inhibitors include JNJ-3133 and abatacept.

Beta adrenoceptor antagonists include NM-001.

BTK inhibitors include GS-4059.

Calcineurin inhibitors: include tacrolimus, and ciclosporin.

Carbohydrate metabolism modulators include ASD-003.

Cathepsin S inhibitors include VBY-129.

CCR9 chemokine antagonists include CCX-507.

CD233 modulators include GSK-2831781.

CD29 modulators include PF-06687234.

CD3 antagonists include NI-0401.

CD4 antagonists include IT-1208.

CD40 ligand inhibitors include SAR-441344, and letolizumab.

CD40 gene inhibitors include NJA-730.

CD40 ligand receptor antagonists include FFP-104, BI-655064.

Chaperonin binding immunoglobulin protein includes IRL-201805.

Chemokine CXC ligand inhibitors include LY-3041658.

CHST15 gene inhibitors include STNM-01.

Collagen modulators include ECCS-50 (DCCT-10).

COT protein kinase inhibitors include GS-4875.

CSF-1 antagonists include JNJ-40346527 (PRV-6527), and SNDX-6352.

CX3CR1 chemokine modulators include E-6130.

Ecobiotics include SER-287.

Eotaxin ligand inhibitors include bertilimumab.

EP4 prostanoid receptor agonists include KAG-308.

F1F0 ATP synthase modulators include LYC-30937 EC.

Fractalkine ligand inhibitors include quetmolimab (E-6011).

Free fatty acid receptor 2 antagonists include GLPG-0974.

GATA 3 transcription factor inhibitors include SB-012.

Glucagon-like peptide 2 agonists include teduglutide, and apraglutide.

Glucocorticoid receptor agonists include budesonide, beclomethasonedipropionate, and dexamethasone sodium phosphate.

Glucocorticoid receptor modulators/TNF ligand inhibitors includeABBV-3373.

Guanylate cyclase receptor agonists include dolcanatide.

HIF prolyl hydroxylase inhibitors include DS-1093, and AKB-4924.

HIF prolyl hydroxylase-2 inhibitors/hypoxia inducible factor-1stimulators include GB-004.

Histone deacetylase inhibitors include givinostat.

Histone deacetylase-6 inhibitors include CKD-506.

HLA class II antigen modulators include HLA class II protein modulators.

ICAM1 gene inhibitors include alicaforsen.

IL-12 antagonists include ustekinumab (IL12/IL23).

IL-13 antagonists include tralokinumab.

IL-18 antagonists include GSK-1070806

IL-22 agonists include RG-7880.

IL-23 antagonists include tildrakizumab, risankizumab (BI-655066),mirikizumab (LY-3074828), brazikumab (AMG-139), and PTG-200.

IL-23A inhibitors include guselkumab.

IL-6 antagonists include olokizumab.

IL-7 receptor antagonists include OSE-127.

IL-8 receptor antagonists include clotrimazole.

Integrin alpha-4/beta-1 antagonists include natalizumab.

Integrin alpha-4/beta-7 antagonists include etrolizumab (a4b7/aEb7),vedolizumab, carotegast methyl, TRK-170 (a4b7/a4b1), PN-10943, andPTG-100.

Integrin antagonists include E-6007.

Interleukin ligand inhibitors include bimekizumab (IL-17A/IL-17F).

Interleukin receptor 17A antagonists include brodalumab.

Interleukin-1 beta ligands include K(D)PT.

Interleukin 1 like receptor 2 inhibitors include BI-655130.

IL-6 receptor modulators include olamkicept.

JAK tyrosine kinase inhibitors include tofacitinib (1/3), peficitinib(1/3), TD-3504, an TD-1473. Jak1 tyrosine kinase inhibitors include acompound disclosed in WO2008/109943. Examples of other JAK inhibitorsinclude, but are not limited to, AT9283, AZD1480, baricitinib,BMS-911543, fedratinib, filgotinib (GLPG0634), gandotinib (LY2784544),INCB039110, lestaurtinib, momelotinib (CYT0387), NS-018, pacritinib(SB1518), peficitinib (ASP015K), ruxolitinib, tofacitinib (formerlytasocitinib), XL019, upadacitinib (ABT-494), filgotinib, GLPG-0555,SHR-0302, and brepocitinib (PF-06700841) (JAK1/Tyk2).

Jak3 tyrosine kinase inhibitors include PF-06651600.

Lactoferrin stimulators include recombinant human lactoferrin (VEN-100).

LanC like protein 2 modulators include BT-11.

Leukocyte elastase inhibitors/Leukocyte proteinase-3 inhibitors includetiprelestat.

MAdCAM inhibitors include SHP-647 (PF-547659).

Melanin concentrating hormone (MCH-1) antagonists include CSTI-100.

Melanocortin MC1 receptor agonists include ASP-3291, and PL-8177.

Metalloprotease-9 inhibitors include GS-5745.

Microbiome modulator include ABI-M201.

Natriuretic peptide receptor C agonists include plecanatide.

Neuregulin-4 ligands include NRG-4.

NKG2 D activating NK receptor antagonists include JNJ-4500.

NLPR3 inhibitors include dapansutrile, BMS-986299, SB-414, MCC-950,IFM-514, JT-194, PELA-167, and NBC-6.

Farnesoid X receptor (FXR and NR1H4) agonists or modulators includeAGN-242266, cilofexor tromethamine (GS-9674), EDP-305, EYP-001,GNF-5120, MET-409, nidufexor (LMB-763), obeticholic acid, TERN-101, andtropifexor.

Nuclear factor kappa B inhibitors include Thetanix.

Opioid receptor antagonists include naltrexone, and IRT-103.

OX40 ligand inhibitors include KHK-4083.

Oxidoreductase inhibitors include olsalazine.

Pellino homolog 1 inhibitors include BBT-401.

P2X7 purinoceptor modulators include SGM-1019.

PDE 4 inhibitors include apremilast.

PPAR alpha/delta agonists include elafibranor (GFT-1007).

PPAR gamma agonists include GED-0507-34-Levo.

Protein fimH inhibitors include sibofimloc (EB-8018).

P-selectin glycoprotein ligand-1 inhibitors include SEL-K2, AbGn-168H,and neihulizumab.

Ret tyrosine kinase receptor inhibitors include GSK-3179106.

RIP-1 kinase inhibitors include GSK-2982772.

RIP-2 kinase inhibitors include GSK-2983559.

Sphingosine 1 phosphate phosphatase 1 stimulators include etrasimod.

Sphingosine-1-phosphate receptor-1 agonists include ozanimod. mocravimod(KRP-203), and BMS-986166.

Sphingosine-1-phosphate receptor-1 agonists/Sphingosine-1-phosphatereceptor-5 agonists include ozanimod.

Sphingosine-1-phosphate receptor-1 antagonists include amiselimod(MT-1303).

Sphingosine-1-phosphate receptor-1 modulators include OPL-002.

Stem cell antigen-1 inhibitors include Ampion (DMI-9523).

Superoxide dismutase modulators include midismase.

Syk inhibitors include GS-9876.

Tissue transglutaminase inhibitor includes zampilimab.

TLR-3 antagonists include PRV-300.

TLR-4 antagonists include JKB-122.

Toll-like receptor 8 (TLR8) inhibitors include E-6887, IMO-4200,IMO-8400, IMO-9200, MCT-465, MEDI-9197, motolimod, resiquimod, VTX-1463,and VTX-763.

TLR-9 agonists include cobitolimod, IMO-2055, IMO-2125, lefitolimod,litenimod, MGN-1601, and PUL-042.

TNF alpha ligand inhibitors include adalimumab, certolizumab pegol,infliximab, golimumab, DLX-105, Debio-0512, HMPL-004, CYT-020-TNFQb,Hemay-007. and V-565.

TNF antagonists include AVX-470, tulinercept, and etanercept.

TPL-2 inhibitors include GS-4875.

Tumor necrosis factor 14 ligand modulators include AEVI-002.

Tumor necrosis factor 15 ligand inhibitors include PF-06480605.

Tyk2 tyrosine kinase inhibitors include PF-06826647, and BMS-986165.

TrkA receptor antagonist includes SNA-125.

Type I IL-1 receptor antagonists include anakinra.

Zonulin inhibitors include larazotide acetate.

Included herein are methods of treatment in which a compound describedherein is administered in combination with an anti-inflammatory agent.Anti-inflammatory agents include but are not limited to NSAIDs,non-specific and COX-2 specific cyclooxgenase enzyme inhibitors, goldcompounds, corticosteroids, methotrexate, tumor necrosis factor receptor(TNF) receptors antagonists, immunosuppressants and methotrexate.

Examples of NSAIDs include, but are not limited to ibuprofen,flurbiprofen, naproxen and naproxen sodium, diclofenac, combinations ofdiclofenac sodium and misoprostol, sulindac, oxaprozin, diflunisal,piroxicam, indomethacin, etodolac, fenoprofen calcium, ketoprofen,sodium nabumetone, sulfasalazine, tolmetin sodium, andhydroxychloroquine. Examples of NSAIDs also include COX-2 specificinhibitors (i.e., a compound that inhibits COX-2 with an IC₅₀ that is atleast 50-fold lower than the IC₅₀ for COX-1) such as celecoxib,valdecoxib, lumiracoxib, etoricoxib and/or rofecoxib.

In a further embodiment, the anti-inflammatory agent is a salicylate.Salicylates include but are not limited to acetylsalicylic acid oraspirin, sodium salicylate, and choline and magnesium salicylates.

The anti-inflammatory agent may also be a corticosteroid. For example,the corticosteroid may be chosen from cortisone, dexamethasone,methylprednisolone, prednisolone, prednisolone sodium phosphate, andprednisone.

In some embodiments, the anti-inflammatory therapeutic agent is a goldcompound such as gold sodium thiomalate or auranofin.

In some embodiments, the anti-inflammatory agent is a metabolicinhibitor such as a dihydrofolate reductase inhibitor, such asmethotrexate or a dihydroorotate dehydrogenase inhibitor, such asleflunomide.

In some embodiments, the anti-inflammatory compound is an anti-C5monoclonal antibody (such as eculizumab or pexelizumab), a TNFantagonist, such as entanercept, or infliximab, which is an anti-TNFalpha monoclonal antibody.

Included herein are methods of treatment in which a compound describedherein, is administered in combination with an immunosuppressant. Insome embodiments, the immunosuppressant is methotrexate, leflunomide,cyclosporine, tacrolimus, azathioprine, or mycophenolate mofetil.

Included herein are methods of treatment in which a compound describedherein, is administered in combination with a class of agent fortreatment of IBD. Examples of classes of agents for treatment of IBDthat can be used in combination with a compound described herein includeASK1 inhibitors, beta adrenoceptor antagonists, BTK inhibitors,beta-glucuronidase inhibitors, bradykinin receptor modulators,calcineurin inhibitors, calcium channel inhibitors, cathepsin Sinhibitors, CCR3 chemokine antagonists, CD40 ligand receptorantagonists, chemokine CXC ligand inhibitors, CHST15 gene inhibitors,collagen modulators, CSF-1 antagonists, cyclooxygenase inhibitors,cytochrome P450 3A4 inhibitors, eotaxin ligand inhibitors, EP4prostanoid receptor agonists, erythropoietin receptor agonists,fractalkine ligand inhibitors, free fatty acid receptor 2 antagonists,GATA 3 transcription factor inhibitors, glucagon-like peptide 2agonists, glucocorticoid agonists, guanylate cyclase receptor agonists,histone deacetylase inhibitors, HLA class II antigen modulators, IL-12antagonists, IL-13 antagonists, IL-23 antagonists, IL-6 antagonists,IL-6 receptor modulators, interleukin-7 receptor modulators, IL-7antagonists, IL-8 antagonists, integrin alpha-4/beta-1 antagonists,integrin alpha-4/beta-7 antagonists, integrin alpha-E antagonists,integrin antagonists, integrin beta-7 antagonists, interleukin ligandinhibitors, interleukin-2 ligand, interleukin receptor 17A antagonists,interleukin-1 beta ligands, interleukin-1 beta ligand modulators, IRAK4inhibitors, JAK tyrosine kinase inhibitors, Jak1 tyrosine kinaseinhibitors, Jak3 tyrosine kinase inhibitors, LanC like protein 2modulators, lipoxygenase modulators, MAdCAM inhibitors, matrixmetalloprotease inhibitors, melanocortin agonists, metalloprotease-9inhibitors, natriuretic peptide receptor C agonists, neuregulin-4ligands, NKG2 D activating NK receptor antagonists, opioid receptorantagonists, opioid receptor delta antagonists, oxidoreductaseinhibitors, P2X7 purinoceptor agonists, PDE 4 inhibitors, phagocytosisstimulating peptide modulators, potassium channel inhibitors, PPAR alphaagonists, PPAR delta agonists, PPAR gamma agonists, protein fimHinhibitors, P-selectin glycoprotein ligand-1 inhibitors, RNA polymeraseinhibitors, sphingosine 1 phosphate phosphatase 1 stimulators,sphingosine 1 phosphate phosphatase modulators, sphingosine-1-phosphatereceptor-1 agonists, sphingosine-1-phosphate receptor-1 antagonists,sphingosine-1-phosphate receptor-1 modulators, sphingosine-1-phosphatereceptor-5 modulators, STAT3 gene inhibitors, stem cell antigen-1inhibitors, superoxide dismutase modulators, superoxide dismutasestimulators, SYK inhibitors, TGF beta 1 ligand inhibitors, thymulinagonists, TLR antagonists, TLR agonists, TNF alpha ligand inhibitors,TNF antagonists, tumor necrosis factor 14 ligand modulators, type II TNFreceptor modulators, TpI 2 inhibitors, and Zonulin inhibitors.

Included herein are methods of treatment in which a compound describedherein is administered in combination with an agent for treatment ofIBD. Examples of agents for treatment of IBD that can be used incombination with a compound described herein, or a pharmaceuticallyacceptable salt, stereoisomer, mixture of stereoisomers, tautomer, ordeuterated analog thereof, include those provided herein for thetreatment of an inflammatory disease or condition, and ABX-464,adalimumab; alicaforsen, ALLO-ASC-CD, AMG-966, anakinra, apremilast;Alequel; AMG-139; amiselimod, ASD-003, ASP-3291, AX-1505, BBT-401,balsalazide; beclomethasone dipropionate; BI-655130, BMS-986184;budesonide; CEQ-508; certolizumab; ChAdOx2-HAV, dexamethasone sodiumphosphate, DNVX-078, etanercept; cibinetide; Clostridium butyricum;ETX-201, golimumab; GS-4997, GS-9876, GS-4875, GS-4059, infliximab;mesalazine, HLD-400, LYC-30937 EC; IONIS-JBI1-2.5Rx, JNJ-64304500,JNJ-4447, naltrexone; natalizumab; neihulizumab, olsalazine; PH-46-A,propionyl-L-carnitine; PTG-100; remestemcel-L; tacrolimus; teduglutide;tofacitinib; ASP-1002; ustekinumab; vedolizumab; AVX-470; INN-108;SGM-1019; PF-06480605; PF-06651600; PF-06687234; RBX-8225, SER-287;Thetanix; TOP-1288; VBY-129; 99mTc-annexin V-128; bertilimumab; DLX-105;dolcanatide; FFP-104; filgotinib; foralumab; GED-0507-34-Levo;givinostat; GLPG-0974; iberogast; JNJ-40346527; K(D)PT; KAG-308;KHK-4083; KRP-203; larazotide acetate; LY-3074828, midismase;olokizumab; OvaSave; P-28-GST; PF-547659; prednisolone; QBECO; RBX-2660,RG-7835; JKB-122; SB-012; STNM-01; Debio-0512; TRK-170; zucapsaicin;ABT-494; Ampion; BI-655066; carotegast methyl; cobitolimod; elafibranor;etrolizumab; GS-5745; HMPL-004; LP-02, ozanimod; peficitinib;quetmolimab (E-6011); RHB-104; rifaximin; tildrakizumab; tralokinumab;brodalumab; laquinimod; plecanatide; vidofludimus; and AZD-058.

Included herein are methods of treatment in which a compound describedherein is administered in combination with an agent for treatment ofgraft versus host disease. Examples of agents for treatment of graftversus host disease that can be used in combination with a compounddescribed herein include those provided herein for the treatment of aninflammatory disease or condition, and [18F]F-AraG, AM-01, Alpha 1antitrypsin stimulator: AAT-IV and CSL-964; Allocetra, efavaleukin alfa(AMG-592), arsenic trioxide, ATIR-101, belatacept, belimumab, betalactamase modulator: ribaxamase, bortezomib, brentuximab vedotin,brimonidine, brimonidine tartrate, cannabidiol, ciclosporin, CYP-001,um, dilanubicel, dornase alfa, DSM-9843, eculizumab, EDP-1066,everolimus, Furestem, GL-101, ibrutinib, IMSUT-CORD, IRX-4204,itolizumab, KD-025, MaaT-013, milatuzumab, mizoribine, mycophenolatemofetil, MSCTC-0010, nalotimagene carmaleucel, MET-2, nilotinib,narsoplimab (OMS-721), pacritinib, PF-05285401, ProTmune, QPI-1002,remestemcel-L, RGI-2001, saratin, SCM-CGH, sirolimus, T-allo10,telmisartan, TOP-1288, TZ-101, voclosporin; CCR5 chemokine antagonist:leronlimab (PRO-140); CD40 ligand receptor antagonist: iscalimab;Complement Cis subcomponent inhibitor: CE-1145, sutimlimab, Cinryze,BIVV-009; B-lymphocyte antigen CD20 inhibitor: obinutuzumab, rituximab;CASP9 gene stimulator: rivogenlecleucel; CD3 antagonist or CD7inhibitor: T-Guard; Complement C5a factor inhibitor: olendalizumab;Dipeptidyl peptidase IV inhibitor: begelomab; JAK1/2 tyrosine kinaseinhibitor: ruxolitinib; Jak1 tyrosine kinase inhibitor: itacitinib;Interleukin-2 ligand: aldesleukin; Interleukin 22 ligand: F-652; IL-2receptor alpha subunit inhibitor: basiliximab and inolimomab; IL-6receptor agonist: PLX-1; IL-6 receptor antagonist: clazakizumab; OX40ligand inhibitor: KY-1005; An example of such OX40 inhibitor is acompound disclosed in U.S. Pat. No. 8,450,460, the entire contents ofwhich are incorporated herein by reference; Signal transducer CD24modulator: CD24-IgFc; Somatostatin receptor agonist: Thymoglobulin; andsphingosine-1-phosphate receptor-1 agonist: ponesimod.

Included herein are methods of treatment in which a compound describedherein is administered in combination with an agent for treatment ofprimary sclerosing cholangitis. Examples of agents for treatment ofprimary sclerosing cholangitis that can be used in combination withcompounds described herein include those provided herein for thetreatment of an inflammatory disease or condition, and BTT-1023, CM-101,Doconexent, GRI-0124, HTD-1801, HTD-2802, hymecromone, IDN-7314,NGM-282, norursodeoxycholic acid, ORBCEL-C, integrin alpha-V/beta-1 andbeta-6 antagonist: PLN-74809; PPAR delta agonist: seladelpar lysine;SCT-5-27, PTGS2 gene and TGF beta 1 gene inhibitor: SCT-5-27, andSTP-705; Farnesoid X receptor (FXR, NR1H4) agonists or modulators:AGN-242266, cilofexor tromethamine (GS-9674), EDP-305, EYP-001,GNF-5120, MET-409, nidufexor (LMB-763), obeticholic acid, TERN-101,tropifexor; liver X receptor antagonist: DUR-928; and CCR5/CCR2chemokine antagonist: cenicriviroc.

In some embodiments, the one or more additional therapeutic agents isselected from the group consisting of: combination drugs for HIV, otherdrugs for treating HIV, HIV protease inhibitors, HIV non-nucleoside ornon-nucleotide inhibitors of reverse transcriptase, HIV nucleoside ornucleotide inhibitors of reverse transcriptase, HIV integraseinhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors,HIV entry inhibitors, HIV maturation inhibitors, latency reversingagents, compounds that target the HIV capsid, immune-based therapies,phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies,bispecific antibodies and “antibody-like” therapeutic proteins, HIV p17matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl cis-transisomerase A modulators, protein disulfide isomerase inhibitors,complement C5a receptor antagonists, DNA methyltransferase inhibitor,HIV vif gene modulators, Vif dimerization antagonists, HIV-1 viralinfectivity factor inhibitors, TAT protein inhibitors, HIV-1 Nefmodulators, Hck tyrosine kinase modulators, mixed lineage kinase-3(MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors,integrin antagonists, nucleoprotein inhibitors, splicing factormodulators, COMM domain containing protein 1 modulators, HIVribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors,dendritic ICAM-3 grabbing nonintegrin 1 inhibitors, HIV GAG proteininhibitors, HIV POL protein inhibitors, Complement Factor H modulators,ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclindependent kinase inhibitors, proprotein convertase PC9 stimulators, ATPdependent RNA helicase DDX3X inhibitors, reverse transcriptase primingcomplex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokineticenhancers, HIV gene therapy, and HIV vaccines, or a pharmaceuticallyacceptable salt of any of the foregoing, or any combinations thereof.

In some embodiments, the one or more additional therapeutic agents isselected from the group consisting of HIV protease inhibiting compounds,HIV non-nucleoside inhibitors of reverse transcriptase, HIVnon-nucleotide inhibitors of reverse transcriptase, HIV nucleosideinhibitors of reverse transcriptase, HIV nucleotide inhibitors ofreverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerizationinhibitors, pharmacokinetic enhancers, and other drugs for treating HIV,or a pharmaceutically acceptable salt of any of the foregoing, or anycombinations thereof.

In some embodiments, the one or more additional therapeutic agent is animmune modulating agent, e.g., an immunostimulant or animmunosuppressant. In certain other embodiments, an immune modulatingagent is an agent capable of altering the function of immunecheckpoints, including the CTLA-4, LAG-3, B7-H3, B7-H4, Tim3, BTLA, KIR,A2aR, CD200 and/or PD-1 pathways. In other embodiments, the immunemodulating agent is immune checkpoint modulating agents. Exemplaryimmune checkpoint modulating agents include anti-CTLA-4 antibody (e.g.,ipilimumab), anti-LAG-3 antibody, anti-B7-H3 antibody, anti-B7-H4antibody, anti-Tim3 antibody, anti-BTLA antibody, anti-KIR antibody,anti-A2aR antibody, anti CD200 antibody, anti-PD-1 antibody, anti-PD-L1antibody, anti-CD28 antibody, anti-CD80 or -CD86 antibody, anti-B7RP1antibody, anti-B7-H3 antibody, anti-HVEM antibody, anti-CD137 or -CD137Lantibody, anti-OX40 or -OX40L antibody, anti-CD40 or -CD40L antibody,anti-GAL9 antibody, anti-IL-10 antibody and A2aR drug. For certain suchimmune pathway gene products, the use of either antagonists or agonistsof such gene products is contemplated, as are small molecule modulatorsof such gene products. In some embodiments, immune modulating agentsinclude those agents capable of altering the function of mediators incytokine mediated signaling pathways.

In some embodiments, a compound as disclosed herein (e.g., a compounddescribed herein may be combined with one or more (e.g., one, two,three, four, one or two, one to three, or one to four) additionaltherapeutic agents in any dosage amount of the compound described herein(e.g., from 10 mg to 1000 mg of compound).

A compound described herein may be combined with the agents providedherein in any dosage amount of the compound (e.g., from 50 mg to 500 mgof compound) the same as if each combination of dosages werespecifically and individually listed.

In some embodiments, provided are kits comprising a pharmaceuticalcomposition comprising a compound described herein or a compounddescribed herein and at least one additional therapeutic agent, or apharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable carrier. In some embodiments, kitscomprising a compound disclosed herein, or a pharmaceutically acceptablesalt, stereoisomer, mixture of stereoisomers, tautomer, or deuteratedanalog thereof, in combination with one or more (e.g., one, two, three,four, one or two, or one to three, or one to four) additionaltherapeutic agents are provided. Any pharmaceutical composition providedin the present disclosure may be used in the kits, the same as if eachand every composition were specifically and individually listed for usein a kit. In some embodiments, the kit comprises instructions for use inthe treatment of an inflammatory disease or condition. In someembodiments, the instructions in the kit are directed to use of thepharmaceutical composition for the treatment of IBD.

List of Abbreviations and Acronyms

Abbreviation Meaning % Percent ° C. Degree Celsius Ac Acetyl AcOH Aceticacid ACN/CH₃CN/ Acetonitrile MeCN ADME Absorption, distribution,metabolism and excretion AIBN 2,2′-Azobis(2-methylpropionitrile) Aq.Aqueous ASK Apoptosis signal-regulating kinase Bicarb Bicarbonate BnBenzyl BOC/Boc Tert-butyloxycarbonyl Bpin Pinacolborane br Broad CASChemical Abstract Service cataCXium A Di(1-adamantyl)-n-butylphosphineCNS Central nervous system COPD Chronic obstructive pulmonary diseaseCREST Calcinosis, Raynaud's syndrome, esophageal dysmotility,sclerodactyly and telangiectasia CVP Cyclophosphamide, vincristine,prednisone d Doublet D/d Deuterium DAST Diethylaminosulfur trifluorideDABCO ® 1,4-Diazabicyclo[2.2.2]octane DCC N,N′-DicyclohexylcarbodiimideDCE Dichloroethane DCM Dichloromethane/methylene chloride dd Doublet ofdoublets DIEA N,N-Diisopropylethylamine DIPEA N,N-DiisopropylethylamineDMA N,N-Dimethylacetamide DMAP 4-Dimethylaminopyridine DME Dimethoxyethane DMF Dimethylformamide DMPK Drug metabolism and pharmacokineticsDMSO Dimethylsulfoxide DPPA Diphenylphosphoryl azide dppf1,1′-Bis(diphenylphosphino)ferrocene dppp1,3-Bis(diphenylphosphino)propane EC₅₀ The half maximal effectiveconcentration equiv/eq Equivalents EA Ethyl acetate Et Ethyl Et₂ODiethyl ether EtOAc/AcOEt Ethyl acetate EtOH Ethanol F. Fahrenheit FBSFetal bovine serum g Grams Gp Glycoprotein h/hr Hours HATU(1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium3-oxid hexafluorophosphate) hex Hexanes HPLC High pressure liquidchromatography Hz Hertz IL Interleukin IUPAC International Union of Pureand Applied Chemistry J Coupling constant (MHz) JAK Janus kinase Kg/kgKilogram KOAc Potassium acetate L Liter LCMS/LC-MS Liquidchromatography-mass spectrometry LHMDS Lithium hexamethyl disilazideLiMg-TMP 2,2,6,6-Tetramethylpiperidinylmagnesium chloride lithiumchloride complex M Molar m multiplet M+ Mass peak M + H Mass peak plushydrogen m-CPBA Meta-Chloroperbenzoic acid Me Methyl Me₂N DimethylamineMeI Methyl Iodide MeOH Methanol MeOTs Methyl Tosylate mg Milligram MHzMegahertz min/m Minute ml/mL Milliliter mM Millimolar mmol Millimole molMole MS Mass spectroscopy MS Multiple sclerosis MsCl Methanesulfonylchloride MTBE Methyl tert-Butyl ether M/Z Mass/Charge N Normal NADHNicotinamide adenine dinucleotide in reduced form NaOH Sodium hydroxideNBS N-Bromosuccinimide ng Nanograms NIS N-Iodosuccinimide nM NanomolarNMR Nuclear magnetic resonance ON Overnight PEG Polyethylene glycol PETPositron emission tomography Ph Phenyl PhMe Toluene PhNO₂ NitrobenzenePhNTf₂ N-Phenyl triflamide pH Expressing the acidity or alkalinity of asolution prep Preparative RA Rheumatoid arthritis Rf Retention factorRPM Revolutions per minute RT/r Room temperature RuPhos2-Dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl s Second s Singletsat. Saturated SFC Super-critical fluid chromatography SLE Systemiclupus erythematosus SPECT Single-photon emission computed tomographySPhos Pd G3 (2-Dicyclohexylphosphino-2′,6′-dimethoxybiphenyl) [2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate SYK Spleentyrosine kinase t Triplet TBACl Tetrabutylammonium chloride TBS/TBDMSTert-butyldimethylsilyl2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethylaminium TBTUtetrafluoroborate tBuOH Tert-butanol tBuBrettPhos[(2-Di-tert-butylphosphino-3,6-dimethoxy-2′,4′,6′- Pd G3triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′- biphenyl)]palladium(II)methanesulfonate TCA Trichloroacetic acid TEA/NEt₃ Triethylamine temp.Temperature TES Triethylsilane TFA Trifluoroacetic acid TFAATrifluoroacetic acid anhydride THF Tetrahydrofuran TLC Thin-layerchromatography TMP Tetramethyl piperidine TMS Trimethylsilyl Tol TolueneTPL2 Tumor Progression Locus 2 Kinase Trityl Triphenylmethyl Vac Vacuumw/v Weight/volume w/w Weight/weight XPhos Pd G3(2-Dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate δChemical shift (ppm) μg Microgram μL/μl Microliter μM Micromolar μmMicrometer μmol Micromole

Synthesis

The compounds of the disclosure may be prepared using methods disclosedherein and routine modifications thereof which will be apparent giventhe disclosure herein and methods well known in the art. Conventionaland well-known synthetic methods may be used in addition to theteachings herein. The synthesis of typical compounds of formula (I),e.g., compounds having structures described by one or more of formula(I), or other formulas or compounds disclosed herein, or apharmaceutically acceptable salt, stereoisomer, mixture ofstereoisomers, tautomer, or deuterated analog thereof, may beaccomplished as described in the following examples.

Salts, such as TFA salts, can be converted to the free-bases/acids orother pharmaceutically acceptable salts.

General Schemes

Typical embodiments of compounds in accordance with the presentdisclosure may be synthesized using the general reaction schemes and/orexamples described below. It will be apparent given the descriptionherein that the general schemes may be altered by substitution of thestarting materials with other materials having similar structures toresult in products that are correspondingly different. Descriptions ofsyntheses follow to provide numerous examples of how the startingmaterials may vary to provide corresponding products. Starting materialsare typically obtained from commercial sources or synthesized usingpublished methods for synthesizing compounds which are embodiments ofthe present disclosure, inspection of the structure of the compound tobe synthesized will provide the identity of each substituent group. Theidentity of the final product will generally render apparent theidentity of the necessary starting materials by a simple process ofinspection, given the examples herein.

Scheme 1 describes a general route that was used to prepare somecompounds of Formula (I). From Intermediate AA1 that has hydroxyl orhalogen group as Z, and halogen group as X, amino acid esters (AA2) canbe prepared under a variety of conditions (eg. Schollkopf, Maruoka,etc). After appropriate protection of the free amine with protectinggroups (PG), eg. Trityl, Boc, etc., AA2 was converted to a boronic acidor boronic ester (AA3) under standard conditions (eg. Miyaura). R¹ wasintroduced under a variety of cross coupling conditions to give AA4.After removal of the amine protecting group (PG) under appropriateconditions, the amine was coupled with acids to provide heterocycliccompounds AA5.

Scheme 2 describes a general route that was used to prepare somecompounds of Formula (I). From Intermediate BB1 that has a halogen groupas Z, amino acid esters (BB2) can be prepared under a variety ofconditions (primarily by Negishi). After appropriate removal of theprotecting group (eg. benzyloxycarbonyl, CBZ), BB2 was converted to thefree amine (BB3) under standard conditions (eg. Pd/H₂). R¹ wasintroduced under a variety of urea forming conditions with appropriatecarboxylic acid or amines to give BB4. After removal of the amineprotecting group (PG) under appropriate conditions, the amine wascoupled with carboxylic acids or acid chlorides to provide heterocycliccompounds BB5.

EXAMPLES Example 1

Synthesis of 8-bromo-5-methylquinoline (1A): To a stirred solution of2-bromo-5-methyl aniline (1200 g, 6.45 mol) in nitrobenzene (660 mL) and75% H₂SO₄ (3.6 L) was added glycerol (1180 g, 6.45 mol) at RT and thenslowly heated to 150° C. for 3 h. The mixture was cooled to RT andpoured into ice-water while maintaining the temperature below 10° C. ThepH was adjusted ˜10 with aqueous 10N NaOH and the product was extractedwith ethyl acetate. The combined organic layer was washed with brine,dried over anhydrous Na₂SO₄ and concentrated under vacuum to affordmaterial that was dissolved in DCM/hexanes (5:1) and stirred for 30minutes. The solid was filtered off and the filtrate was evaporatedunder reduced pressure to afford 1A.

Synthesis of 8-bromo-5-(bromomethyl)quinoline (1B): To a stirredsolution of compound 1A (500 g, 2.25 mol) in benzene (7.5 L) was addedNBS (481 g, 2.7 mol) at RT. The reaction mixture was heated to 80° C.under tungsten light for 12 h. The reaction was cooled to RT, wateradded and extracted with ethyl acetate. The organic layer was separated,washed with water, brine, and dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. This material was triturated with20% ethyl acetate in hexane at RT. The material was filtered, washedwith hexane and dried under reduced pressure to afford 1B.

Synthesis of methyl(S)-3-(8-bromoquinolin-5-yl)-2-((diphenylmethylene)amino) propanoate(1C): To a stirred solution of 1B (392 g, 1.3 mol) in DCM (9 L) wasadded (−)-cinchonidine (35 g, 0.12 mol) at RT. The reaction mixture wascooled to 10° C., KOH (2.4 L, 50% aq) was added followed by methyl2-((diphenylmethylene)amino) acetate (300 g, 1.2 mol). The reactionmixture was allowed to stir at RT for 6 h. The reaction mixture wasdiluted with water and stirred for 15 minutes. DCM was added and theorganic layer was washed with brine, dried over anhydrous Na₂SO₄, andconcentrated under reduced pressure. This material was purified by100-200 mesh silica gel column chromatography and eluted with 10-15%ethyl acetate in hexane afforded compound 1C.

Synthesis of methyl (S)-2-amino-3-(8-bromoquinolin-5-yl)propanoate (1D):To a stirred solution of 1C (400 g, 845 mmol) in methanol (2 L) wasadded HCl in 1,4-dioxane (2.8 L, 4N) keeping the temperature below 5° C.The reaction mixture was allowed to stir at RT for 48 h. The reactionmixture was concentrated under reduced pressure, dissolved in water, andwashed with ethyl acetate. The aqueous layer was adjusted to ˜pH 8 usingsat. NaHCO₃ and extracted with DCM. The combined organic layer waswashed with brine, dried over anhydrous Na₂SO₄, and concentrated underreduced pressure to afford a 70:30 mixture of racemic 1D. A suspensionof this material in MTBE was heated to reflux for 1 h. The reactionmixture was cooled to RT, the solid was filtered off and the filtratewas evaporated under reduced pressure to obtain a solid, which was againstirred with MTBE at RT. The solid was filtered off and the filtrate wasevaporated under reduced pressure to afford 1D. This material wasdissolved in ethyl acetate, cooled to 0° C., followed by addition of 4NHCl and allowed to stir at RT for 1 h. The reaction mixture wasconcentrated under reduced pressure and triturated with MTBE to afford1D.

Synthesis of methyl(S)-2-amino-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl) propanoate (1E):To a microwave vial was added 1D (50 mg, 0.145 mmol),(2-chloro-4-cyanophenyl)boronic acid (45 mg, 0.246 mmol), Pd(PPh₃)₄ (8mg, 0.007 mmol), and aq Na₂CO₃ (0.217 mL, 2M) in DME (2 mL). Thereaction mixture was allowed to stir at 120° C. for 20 min. EA and waterwas added to the reaction mixture. The organic layer was washed withbrine, dried over anhydrous Na₂SO₄, and concentrated under reducedpressure. The material was purified by silica gel chromatography using0-30% MeOH in EA to afford the title compound.

Synthesis of methyl(S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2-fluoro-6-methylbenzamido)propanoate(1F): To a stirred solution of 1E (29 mg, 0.08 mmol) in THF (2 mL) wasadded 2-fluoro-6-methylbenzoyl chloride (21 mg, 0.12 mmol) and DIEA(0.07 mL, 0.4 mmol). The reaction mixture was allowed to stir for 1 h,then diluted with DCM and concentrated. The material was purified onsilica gel eluting with MeOH in DCM (0-30%) to give the title compound.

Synthesis of(S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2-fluoro-6-methylbenzamido)propanoicacid (1): To a stirred solution of 1F (35 mg, 0.07 mmol) in THF (3 mL)was added aqueous LiOH (0.35 mL, 0.035 mmol). The reaction mixture wasallowed to stir for 1 h then concentrated under reduced pressure. Thematerial was purified via reverse phase HPLC to afford the titlecompound. MS (m/z) 488.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ 9.03 (d,J=8.4 Hz, 1H), 8.84 (dd, J=4.2, 1.6 Hz, 1H), 8.64 (dd, J=8.7, 1.7 Hz,1H), 8.16 (d, J=1.7 Hz, 1H), 7.90 (d, J=7.9 Hz, 1H), 7.68-7.60 (m, 3H),7.55 (d, J=7.9 Hz, 1H), 7.26 (d, J=6.1 Hz, 1H), 6.99 (d, J=6.7 Hz, 2H),4.82 (t, J=9.9 Hz, 1H), 3.39 (d, J=12.9 Hz, 1H), 2.65 (s, 1H), 2.31 (s,1H), 2.07 (s, 1H), 1.96 (s, 3H).

Example 2

Synthesis of(S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2-chloro-6-fluorobenzamido)propanoic acid (2): The title compound was prepared accordingto the method presented for the synthesis of compound 1F and 1 startingwith 2-chloro-6-fluorobenzoyl chloride and 1E. MS (m/z) 508.1 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d6) δ 9.27 (d, J=8.3 Hz, 1H), 8.84 (dd, J=4.1, 1.6Hz, 1H), 8.65 (dd, J=8.6, 1.7 Hz, 1H), 8.16 (dd, J=1.7, 0.4 Hz, 1H),7.91 (d, J=7.9 Hz, 1H), 7.68-7.60 (m, 3H), 7.54 (d, J=7.9 Hz, 1H), 7.42(td, J=8.3, 6.1 Hz, 1H), 7.30-7.19 (m, 2H), 4.82 (s, 1H), 3.77 (d,J=14.7 Hz, 1H), 3.38 (dd, J=14.6, 10.6 Hz, 1H).

Example 3

Synthesis of methyl(S)-3-(8-bromoquinolin-5-yl)-2-(2,6-difluorobenzamido) propanoate (3A):The title compound was prepared according to the method presented forthe synthesis of compound 1F starting with 2,6-difluorobenzoyl chlorideand 1D.

Synthesis of methyl(S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluorobenzamido)propanoate (3B): The title compound was prepared according tothe method presented for the synthesis of compound 1E starting with 3A.

Synthesis of(S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluorobenzamido)propanoic acid (3): The title compound was prepared accordingto the method presented for the synthesis of compound 1F starting with3B. MS (m/z) 492.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ 9.25 (d, J=8.1Hz, 1H), 8.84 (dd, J=4.1, 1.6 Hz, 1H), 8.64 (dd, J=8.8, 1.7 Hz, 1H),8.15 (d, J=1.7 Hz, 1H), 7.90 (dd, J=8.0, 1.7 Hz, 1H), 7.66-7.61 (m, 3H),7.57 (d, J=7.9 Hz, 1H), 7.53-7.41 (m, 1H), 7.10 (t, J=8.0 Hz, 2H), 4.77(s, 1H), 3.76 (s, 1H), 3.41 (s, 1H).

Example 4

Synthesis of methyl(S)-3-(8-bromoquinolin-5-yl)-2-(2,6-dichlorobenzamido) propanoate (4A):The title compound was prepared according to the method presented forthe synthesis of compound 3A starting with 2,6-dichlorobenzoyl chlorideand 1D.

Synthesis of(S)-(5-(2-(2,6-dichlorobenzamido)-3-methoxy-3-oxopropyl)quinolin-8-yl)boronicacid (4B): To a stirred solution of 4A (0.61 g, 1.4 mmol) in dioxane wasadded bis(pinacolato)diboron (0.42 g, 1.6 mmol), followed by KOAc (0.4g, 4.1 mmol), Pd(dppf)Cl₂ (0.03 g, 0.03 mmol), and cataCXium A (0.04 g,0.08 mmol). The reaction vessel was flushed with nitrogen then heated to100° C. for 4 hrs. EA was added then filtered through Celite andconcentrated under reduced pressure to afford the title compound thatwas used without further purification.

Synthesis of methyl(S)-3-(8-(2,6-dichloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-dichlorobenzamido)propanoate(4C): To a stirred solution 4B (0.08 g, 0.017 mmol) in DME was added4-bromo-3,5-dichlorobenzonitrile (0.08 g, 0.034 mmol), XPhos Pd G3(0.014 g, 0.0017 mmol) and aq. K₃PO₄ (0.6 mL, 1 M). The reaction wasdegassed with nitrogen and heated at 90° C. for 30 min. The reactionmixture was concentrated under reduced pressure to give the titlecompound that was used without further purification.

Synthesis of(S)-3-(8-(2,6-dichloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-dichlorobenzamido)propanoic acid (4): The title compound was prepared accordingto the method presented for the synthesis of compound 1 starting with4C. MS (m/z) 558.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ 9.28 (d, J=8.4Hz, 1H), 8.82 (dd, J=4.2, 1.6 Hz, 1H), 8.65 (dd, J=8.7, 1.6 Hz, 1H),8.25-8.15 (m, 2H), 7.74-7.62 (m, 2H), 7.60 (d, J=7.3 Hz, 1H), 7.45-7.32(m, 3H), 4.83 (ddd, J=11.8, 8.6, 3.7 Hz, 1H), 3.78 (dd, J=14.5, 3.8 Hz,1H), 3.38 (dd, J=14.5, 11.0 Hz, 1H).

Example 5

Synthesis of(S)-(5-(2-(2,6-difluorobenzamido)-3-methoxy-3-oxopropyl)quinolin-8-yl)boronicacid (SA): The title compound was prepared according to the methodpresented for the synthesis of compound 4B of Example 4 starting with3A.

Synthesis of methyl(S)-3-(8-(4,5-dichloro-2-methoxyphenyl)quinolin-5-yl)-2-(2,6-difluorobenzamido)propanoate(SB): To a microwave vial was added 5A (145 mg, 0.234 mmol),1-bromo-4,5-dichloro-2-methoxybenzene (50 mg, 0.195 mmol), Pd(PPh₃)₄ (11mg, 0.01 mmol), and aq Na₂CO₃ (0.293 mL, 2M) in DME (2 mL). The reactionmixture was allowed to stir at 120° C. for 30 min. EA and water wasadded to the reaction mixture. The organic layer was washed with brine,dried over anhydrous Na₂SO₄, and concentrated under reduced pressure toafford the title compound.

Synthesis of(S)-3-(8-(4,5-dichloro-2-methoxyphenyl)quinolin-5-yl)-2-(2,6-difluorobenzamido)propanoicacid (5): The title compound was prepared according to the methodpresented for the synthesis of compound 1 starting with 5B. MS (m/z)530.7 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ 9.27 (d, J=8.1 Hz, 1H), 8.86(dd, J=4.3, 1.6 Hz, 1H), 8.73-8.61 (m, 1H), 7.66 (dd, J=8.6, 4.3 Hz,1H), 7.60 (q, J=7.4 Hz, 2H), 7.52-7.43 (m, 1H), 7.40 (d, J=8.7 Hz, 2H),7.16-7.05 (m, 2H), 4.78-4.70 (m, 1H), 3.74 (dd, J=14.5, 4.4 Hz, 1H),3.64 (s, 3H), 3.39 (dd, J=14.6, 10.1 Hz, 1H), 1.05 (s, 1H).

Example 6

Synthesis of 2-bromo-5-fluoro-1-methoxy-3-(trifluoromethyl)benzene (6A):To a stirred solution of 2-bromo-5-fluoro-3-(trifluoromethyl)phenol(0.21 g, 0.64 mmol) in DMF was added K₂CO₃ (133 mg, 0.96 mmol) andiodomethane (0.105 g, 0.74 mmol). The reaction mixture was allowed tostir at RT. EA and water was added to the reaction mixture. The organiclayer was washed with brine, dried over anhydrous Na₂SO₄, andconcentrated under reduced pressure and purified by silica gelchromatography using hexanes/EA as gradient.

Synthesis of methyl(2S)-2-(2,6-difluorobenzamido)-3-(8-(4-fluoro-2-methoxy-6-(trifluoromethyl)phenyl)quinolin-5-yl)propanoate(6B): The title compound was prepared according to the method presentedfor the synthesis of compound 5B starting with 5A and 6A.

Synthesis of(2S)-2-(2,6-difluorobenzamido)-3-(8-(4-fluoro-2-methoxy-6-(trifluoromethyl)phenyl)quinolin-5-yl)propanoicacid (6): The title compound was prepared according to the methodpresented for the synthesis of compound 1 starting with 6B. MS (m/z)549.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ 9.28 (dd, J=12.4, 8.1 Hz, 1H),8.81 (dd, J=4.2, 1.6 Hz, 1H), 8.67 (d, J=8.7 Hz, 1H), 7.67-7.56 (m, 2H),7.49 (dqd, J=8.2, 6.6, 1.6 Hz, 2H), 7.41-7.34 (m, 1H), 7.29 (dd, J=9.1,2.5 Hz, 1H), 7.11 (ddd, J=8.3, 7.4, 3.8 Hz, 2H), 4.84-4.75 (m, 1H), 3.76(dd, J=31.6, 4.3 Hz, 1H), 3.59 (d, J=5.7 Hz, 3H), 3.42 (ddd, J=21.3,14.6, 10.4 Hz, 1H).

Examples 7 and 8

Preparation of(S)-2-(2,6-difluorobenzamido)-3-((R)-8-(4-fluoro-2-methoxy-6-(trifluoromethyl)phenyl)quinolin-5-yl)propanoicacid (7): 6 was separated into its 2 diastereomeric atropisomers bysupercritical fluid chromatography using 25% EtOH/TFA co-solvent, at aflow rate of 50 mL/min, using an AD-H 5 μm 21×250 mm column. The titlecompound was identified as the first eluting peak. MS (m/z) 549.1[M+H]⁺. 1H NMR (400 MHz, Methanol-d4) δ 9.36 (dd, J=8.7, 1.6 Hz, 1H),8.95 (dd, J=5.0, 1.5 Hz, 1H), 8.00 (dd, J=8.7, 5.0 Hz, 1H), 7.89 (d,J=7.4 Hz, 1H), 7.78 (dd, J=7.4, 0.9 Hz, 1H), 7.45 (tt, J=8.4, 6.4 Hz,1H), 7.32 (s, 1H), 7.30 (s, 1H), 7.02-6.95 (m, 2H), 5.12 (dd, J=9.8, 5.2Hz, 1H), 4.03 (dd, J=14.4, 5.2 Hz, 1H), 3.71-3.63 (m, 4H).

Preparation of(S)-2-(2,6-difluorobenzamido)-3-((S)-8-(4-fluoro-2-methoxy-6-(trifluoromethyl)phenyl)quinolin-5-yl)propanoicacid (8): 6 was separated into its 2 diastereomeric atropisomers bysupercritical fluid chromatography using 25% EtOH/TFA cosolvent, at aflow rate of 50 mL/min, using an AD-H 5 μm 21×250 mm column. The titlecompound was identified as the second eluting peak. MS (m/z) 549.1[M+H]⁺. 1H NMR (400 MHz, Methanol-d4) δ 9.35 (dd, J=8.7, 1.5 Hz, 1H),8.95 (dd, J=5.0, 1.5 Hz, 1H), 7.99 (dd, J=8.6, 5.0 Hz, 1H), 7.86 (d,J=7.4 Hz, 1H), 7.77 (d, J=7.4 Hz, 1H), 7.45 (tt, J=8.6, 6.4 Hz, 1H),7.32 (s, 1H), 7.29 (s, 1H), 7.03-6.96 (m, 2H), 5.14 (dd, J=9.9, 5.0 Hz,1H), 4.04 (dd, J=14.6, 5.1 Hz, 1H), 3.69-3.61 (m, 4H).

Example 9

Synthesis of methyl(S)-2-(2,6-difluorobenzamido)-3-(8-(3-methoxynaphthalen-2-yl)quinolin-5-yl)propanoate(9A): The title compound was prepared according to the method presentedfor the synthesis of compound 5B starting with2-bromo-3-methoxynaphthalene and 5A.

Synthesis of(S)-2-(2,6-difluorobenzamido)-3-(8-(3-methoxynaphthalen-2-yl)quinolin-5-yl)propanoicacid (9): The title compound was prepared according to the methodpresented for the synthesis of compound 1 starting with 9A. MS (m/z)513.0 [M+H]⁺. 1H NMR (400 MHz, DMSO-d6) δ 9.30 (d, J=8.2 Hz, 1H), 8.86(d, J=4.8 Hz, 2H), 7.95-7.83 (m, 2H), 7.81-7.64 (m, 3H), 7.55-7.43 (m,3H), 7.38 (ddd, J=8.1, 6.9, 1.2 Hz, 1H), 7.17-7.08 (m, 2H), 4.80 (ddd,J=10.1, 8.1, 4.4 Hz, 1H), 3.80 (dd, J=14.6, 4.5 Hz, 1H), 3.71 (s, 3H),3.45 (dd, J=14.6, 10.1 Hz, 1H).

Example 10

Synthesis of 1-bromo-2-(cyclopropylmethoxy)-4,5-difluorobenzene (10A):To a stirred solution of 2-bromo-4,5-difluorophenol (1.2 g, 5.5 mmol) inMeCN was added K₂CO₃ (2.3 g, 16.4 mmol) and (bromomethyl)cyclopropane(0.82 g, 6.0 mmol). The reaction mixture was allowed to stir for 2 hr at70° C. EA and water was added to the reaction mixture. The organic layerwas washed with brine, dried over anhydrous Na₂SO₄, concentrated underreduced pressure and purified by silica gel chromatography usinghexanes/EA as gradient.

Synthesis of methyl(S)-3-(8-(2-(cyclopropylmethoxy)-4,5-difluorophenyl)quinolin-5-yl)-2-(2,6-difluorobenzamido)propanoate(10B): The title compound was prepared according to the method presentedfor the synthesis of compound 5B starting with 10A and 5A.

Synthesis of(S)-3-(8-(2-(cyclopropylmethoxy)-4,5-difluorophenyl)quinolin-5-yl)-2-(2,6-difluorobenzamido)propanoicacid (10): The title compound was prepared according to the methodpresented for the synthesis of compound 1 starting with 10B. MS (m/z)538.6 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ 12.81 (s, 1H), 9.28 (d, J=8.1Hz, 1H), 8.89 (d, J=4.1 Hz, 1H), 8.69 (s, 2H), 7.66 (d, J=7.3 Hz, 2H),7.60 (d, J=7.4 Hz, 1H), 7.55-7.45 (m, 1H), 7.37-7.21 (m, 2H), 7.16-7.08(m, 2H), 4.76 (td, J=10.3, 9.2, 4.2 Hz, 1H), 3.78-3.74 (m, 2H), 3.41(dd, J=14.6, 10.0 Hz, 1H), 3.10 (p, J=4.8 Hz, 2H), 0.81 (d, J=4.8 Hz,1H), 0.24 (dt, J=9.0, 2.9 Hz, 2H), −0.01-−0.05 (m, 2H).

Example 11

Synthesis of methyl(S)-2-(2,6-difluorobenzamido)-3-(8-(3,5,6-trimethylpyridin-2-yl)quinolin-5-yl)propanoate(11A): The title compound was prepared according to the method presentedfor the synthesis of compound 4C of Example 4 starting with2-bromo-3,5,6-trimethyl pyridine and 5A.

Synthesis of(S)-2-(2,6-difluorobenzamido)-3-(8-(3,5,6-trimethylpyridin-2-yl)quinolin-5-yl)propanoicacid (II): The title compound was prepared according to the methodpresented for the synthesis of compound 1 starting with 11A. MS (m/z)476.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ 9.33 (d, J=8.3 Hz, 1H), 8.89(dd, J=4.2, 1.6 Hz, 1H), 8.78-8.72 (m, 1H), 8.36 (s, 1H), 7.92 (d, J=7.5Hz, 1H), 7.78-7.69 (m, 2H), 7.49 (tt, J=8.5, 6.6 Hz, 1H), 7.11 (dd,J=8.4, 7.6 Hz, 2H), 4.84-4.74 (m, 1H), 3.85 (dd, J=14.3, 4.2 Hz, 1H),3.43 (dd, J=14.4, 10.4 Hz, 1H), 2.64 (s, 3H), 2.46 (s, 3H), 2.05 (s,3H).

Example 12

Synthesis of methyl(S)-2-(2,6-difluorobenzamido)-3-(8-(5,6-dimethyl-3-(trifluoromethyl)pyridin-2-yl)quinolin-5-yl)propanoate (12A): The title compoundwas prepared according to the method presented for the synthesis ofcompound 4C of Example 4 starting with2-bromo-5,6-dimethyl-3-(trifluoromethyl)pyridine and 5A with Pd XPhosG4.

Synthesis of(S)-2-(2,6-difluorobenzamido)-3-(8-(5,6-dimethyl-3-(trifluoromethyl)pyridin-2-yl)quinolin-5-yl)propanoic acid (12): The title compound wasprepared according to the method presented for the synthesis of compound1 starting with 12A. MS (m/z) 530.1 [M+H]⁺. 1H NMR (400 MHz, DMSO-d6) δ9.28 (d, J=8.1 Hz, 1H), 8.77 (dd, J=4.1, 1.6 Hz, 1H), 8.62 (dd, J=8.7,1.6 Hz, 1H), 8.02 (s, 1H), 7.62-7.54 (m, 3H), 7.52-7.43 (m, 1H), 7.11(dd, J=8.5, 7.5 Hz, 2H), 4.74 (td, J=9.0, 4.3 Hz, 1H), 3.75 (m, 1H),3.40 (m, 1H), 2.50 (s, 3H), 2.41 (s, 3H).

Example 13

Synthesis of methyl(S)-2-(2,6-difluorobenzamido)-3-(8-(4-methoxy-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)quinolin-5-yl)propanoate(13A): The title compound was prepared according to the method presentedfor the synthesis of compound 4C of Example 4 starting with3-bromo-4-methoxy-1-methylpyridin-2(1H)-one and 5A.

Synthesis of(S)-2-(2,6-difluorobenzamido)-3-(8-(4-methoxy-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)quinolin-5-yl)propanoicacid (13): The title compound was prepared according to the methodpresented for the synthesis of compound 1 starting with 13A. MS (m/z)464.1 [M+H]⁺. 1H NMR (400 MHz, DMSO-d6) δ 9.32 (d, J=7.9 Hz, 1H),9.08-8.98 (m, 1H), 8.96 (d, J=4.6 Hz, 1H), 7.95 (d, J=7.7 Hz, 1H),7.91-7.83 (m, 1H), 7.75-7.65 (m, 2H), 7.50 (tt, J=8.4, 6.5 Hz, 1H),7.16-7.08 (m, 2H), 6.49 (dd, J=7.7, 3.5 Hz, 1H), 4.84-4.72 (m, 1H),3.85-3.75 (m, 1H), 3.68 (d, J=7.5 Hz, 3H), 3.55-3.40 (m, 4H).

Example 14

Synthesis of methyl(S)-2-(2,6-difluorobenzamido)-3-(1-methyl-2-oxo-1,2-dihydro-[3,8′-biquinolin]-5′-yl)propanoate(14A): The title compound was prepared according to the method presentedfor the synthesis of compound 4C of Example 4 starting with3-bromo-1-methylquinolin-2(1H)-one and 5A.

Synthesis of(S)-2-(2,6-difluorobenzamido)-3-(1-methyl-2-oxo-1,2-dihydro-[3,8′-biquinolin]-5′-yl)propanoicacid (14): The title compound was prepared according to the methodpresented for the synthesis of compound 1 starting with 14A. MS (m/z)514.1 [M+H]⁺. 1H NMR (400 MHz, DMSO-d6) δ 9.30 (d, J=8.1 Hz, 1H), 8.88(d, J=4.3 Hz, 1H), 8.77 (s, 1H), 7.98 (s, 1H), 7.78 (dd, J=7.8, 1.5 Hz,1H), 7.74 (d, J=7.3 Hz, 1H), 7.70-7.56 (m, 3H), 7.49 (tt, J=8.4, 6.5 Hz,1H), 7.35-7.27 (m, 1H), 7.18-7.08 (m, 2H), 4.75 (td, J=9.5, 4.5 Hz, 1H),3.77 (dd, J=14.5, 4.5 Hz, 1H), 3.68 (s, 3H), 3.44 (dd, J=14.5, 9.9 Hz,1H).

Example 15

Synthesis of methyl(S)-2-(2,6-difluorobenzamido)-3-(5′-fluoro-[8,8′-biquinolin]-5-yl)propanoate(15A): The title compound was prepared according to the method presentedfor the synthesis of compound 3B starting with(5-fluoroquinolin-8-yl)boronic acid and 3A.

Synthesis of(S)-2-(2,6-difluorobenzamido)-3-(5′-fluoro-[8,8′-biquinolin]-5-yl)propanoicacid (15): The title compound was prepared according to the methodpresented for the synthesis of compound 1 starting with 15A. MS (m/z)502.9 [M+H]⁺. 1H NMR (400 MHz, DMSO-d6) δ 9.32 (d, J=8.1 Hz, 1H), 8.74(dd, J=4.2, 1.8 Hz, 1H), 8.70 (s, 1H), 8.56 (d, J=8.7 Hz, 1H), 7.77-7.43(m, 8H), 7.19-7.05 (m, 2H), 4.79 (m, 1H), 3.77-3.65 (m, J=1H), 3.56-3.40(m, 1H).

Example 16

Synthesis of methyl(S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(3-(difluoromethoxy)-2,6-difluorobenzamido)propanoate (16A): To a stirred solutionof 1E (0.15 g, 0.41 mmol) in DCM was added3-(difluoromethoxy)-2,6-difluorobenzoic acid (0.11 g, 0.49 mmol), HATU(0.187 g, 0.49 mmol) and TEA (0.36 mL, 2.1 mmol). The reaction mixturewas allowed to stir for 2 hr at RT. The reaction mixture wasconcentrated under reduced pressure and used without furtherpurification.

Synthesis of(S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(3-(difluoromethoxy)-2,6-difluorobenzamido)propanoicacid (16): The title compound was prepared according to the methodpresented for the synthesis of compound 1 starting with 16A. MS (m/z)559.9 [M+H]⁺. 1H NMR (400 MHz, DMSO-d6) δ 8.16 (m, J=8.4 Hz, 3H), 7.67(d, J=8.5 Hz, 2H), 7.56-7.21 (m, 6H), 4.75 (ddd, J=11.7, 8.4, 3.7 Hz,1H), 3.10 (m, 2H) 2.99 (dd, J=14.3, 11.3 Hz, 1H).

Example 17

Synthesis of(S)-2-(6-chloro-2,3-difluorobenzamido)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)propanoic acid (17): The title compound was preparedaccording to the method presented for the synthesis of compound 1F and 1starting with 6-chloro-2,3-difluorobenzoyl chloride and 1E. MS (m/z)559.9 [M+H]⁺. 1H NMR (400 MHz, DMSO-d6) δ 9.37 (d, J=8.4 Hz, 1H), 8.84(dd, J=4.1, 1.6 Hz, 1H), 8.64 (dd, J=8.6, 1.6 Hz, 1H), 8.16 (dd, J=1.6,0.4 Hz, 1H), 7.91 (d, J=7.8 Hz, 1H), 7.67-7.64 (m, 1H), 7.63 (s, 2H),7.55 (d, J=7.9 Hz, 1H), 7.33 (td, J=8.7, 3.8 Hz, 1H), 4.83 (s, 1H),3.84-3.74 (m, 1H), 3.38 (dd, J=14.6, 10.6 Hz, 1H).

Example 18

Synthesis of(S)-2-(2,6-difluorobenzamido)-3-(8-(4-(ethoxymethyl)-2,6-dimethoxyphenyl)quinolin-5-yl)propanoic acid (18): The title compound wasprepared according to the method presented for the synthesis of compound3B and 3 starting with (4-(ethoxymethyl)-2,6-dimethoxyphenyl)boronicacid and 3A. MS (m/z) 551.1 [M+H]⁺. 1H NMR (400 MHz, DMSO-d6) δ 13.09(s, 1H), 9.30 (d, J=8.1 Hz, 1H), 9.10-8.69 (m, 2H), 7.96-7.30 (m, 4H),7.11 (t, J=8.0 Hz, 2H), 6.75 (d, J=3.4 Hz, 2H), 4.85-4.74 (m, 1H), 4.53(s, 2H), 3.86-3.66 (m, 1H), 3.64-3.53 (m, 8H), 3.45 (dd, J=14.7, 10.1Hz, 1H), 1.21 (t, J=7.0 Hz, 3H).

Example 19

Synthesis of(S)-3-(8-(2,6-dichloro-4-fluorophenyl)quinolin-5-yl)-2-(2,6-difluorobenzamido)propanoic acid (19): The title compound was prepared accordingto the method presented for the synthesis of compound 5B and 5 startingwith 2-bromo-1,3-dichloro-5-fluorobenzene and 5A. MS (m/z) 518.9 [M+H]⁺.1H NMR (400 MHz, DMSO-d6) δ 13.02 (s, 1H), 9.26 (d, J=8.1 Hz, 1H), 8.82(dd, J=4.1, 1.6 Hz, 1H), 8.68-8.58 (m, 1H), 7.70-7.59 (m, 3H), 7.57 (d,J=7.3 Hz, 1H), 7.47 (tt, J=8.5, 6.5 Hz, 1H), 7.15-7.03 (m, 2H), 4.78(ddd, J=10.2, 8.1, 4.4 Hz, 1H), 3.76 (dd, J=14.5, 4.4 Hz, 1H), 3.41 (dd,J=14.6, 10.3 Hz, 1H).

Example 20

Synthesis of(S)-3-(8-(3,5-dichloropyridin-4-yl)quinolin-5-yl)-2-(2,6-difluorobenzamido)propanoic acid (20): The title compound was prepared accordingto the method presented for the synthesis of compound 5B and 5 startingwith 4-bromo-3,5-dichloropyridine and 5A. MS (m/z) 501.9 [M+H]⁺. 1H NMR(400 MHz, DMSO-d6) δ 9.27 (d, J=8.2 Hz, 1H), 8.83 (dd, J=4.1, 1.6 Hz,1H), 8.75 (d, J=2.4 Hz, 2H), 8.66 (dd, J=8.7, 1.7 Hz, 1H), 7.69-7.60 (m,3H), 7.47 (tt, J=8.5, 6.5 Hz, 1H), 7.09 (dd, J=8.4, 7.5 Hz, 2H), 4.80(ddd, J=10.4, 8.2, 4.4 Hz, 1H), 3.78 (dd, J=14.5, 4.4 Hz, 1H), 3.43 (dd,J=14.6, 10.4 Hz, 1H).

Example 21

Synthesis of(S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-methoxybenzamido)propanoicacid (21): The title compound was prepared according to the methodpresented for the synthesis of compound 16A and 16 starting with2,6-difluoro-4-methoxybenzoic acid and 1E. MS (m/z) 523.2 [M+H]⁺. 1H NMR(400 MHz, DMSO-d6) δ 9.41 (s, 1H), 8.62 (s, 1H), 8.30 (s, 1H), 8.15-7.98(m, 4H), 7.11 (d, J=6.7 Hz, 3H), 6.82 (d, J=9.1 Hz, 2H), 6.67 (s, 2H),4.47 (s, 2H), 3.62 (s, 6H), 3.53 (q, J=7.0 Hz, 2H), 3.18 (dd, J=124.4,13.3 Hz, 2H), 1.28 (s, 3H), 1.19 (t, J=7.0 Hz, 3H).

Example 22

Synthesis of(S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-dichloro-4-fluorobenzamido)propanoicacid (22): The title compound was prepared according to the methodpresented for the synthesis of compound 3A, 3B, and 3 starting with2,6-dichloro-4-fluorobenzoyl chloride and 1D. MS (m/z) 541.9 [M+H]⁺. 1HNMR (400 MHz, DMSO-d6) δ 9.26 (d, J=8.5 Hz, 1H), 8.83 (dd, J=4.1, 1.6Hz, 1H), 8.65 (dd, J=8.7, 1.7 Hz, 1H), 8.15 (dd, J=1.6, 0.4 Hz, 1H),7.94-7.87 (m, 1H), 7.69-7.58 (m, 3H), 7.50 (d, J=8.6 Hz, 3H), 4.84 (s,1H), 3.76 (dd, J=14.5, 4.1 Hz, 1H), 3.37 (s, 1H).

Example 23

Synthesis of(S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2-fluoro-6-methoxybenzamido)propanoic acid (23): The title compound was prepared accordingto the method presented for the synthesis of compound 1F and 1 startingwith 2-fluoro-6-methoxy benzoyl chloride and 1E. MS (m/z) 504.2 [M+H]⁺.1H NMR (400 MHz, DMSO-d6) δ 8.92 (d, J=8.1 Hz, 1H), 8.84 (dd, J=4.1, 1.6Hz, 1H), 8.64 (dd, J=8.7, 1.7 Hz, 1H), 8.16 (dd, J=1.6, 0.4 Hz, 1H),7.90 (dd, J=7.9, 1.7 Hz, 1H), 7.68-7.64 (m, 2H), 7.58 (d, J=7.6 Hz, 1H),7.35 (td, J=8.4, 6.8 Hz, 1H), 6.84 (d, J=8.5 Hz, 1H), 6.78 (t, J=8.6 Hz,1H), 4.80-4.68 (m, 1H), 3.69-3.65 (m, 1H), 3.63 (s, 3H), 3.50-3.40 (m,1H).

Example 24

Synthesis of methyl 2,6-difluoro-4-(2-oxopropyl)benzoate (24A): To astirred solution of methyl 4-bromo-2,6-difluorobenzoate (0.15 g, 0.41mmol) in 1,4-dioxane was added acetone (1.8 mL), Pd(OAc)₂ (18 mg, 0.081mmol), Cs₂CO₃ (1.05 g, 3.2 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (93.98 mg, 0.16 mmol). This mixture wasflushed with N₂ for 5 min, then heated to 100° C. for 2.5 hours. Thereaction mixture was filtered through celite, rinsed with EA andpurified by silica gel chromatography using EA in hexanes as eluent togive the title compound.

Synthesis of methyl 2,6-difluoro-4-(2-hydroxypropyl)benzoate (24B): To astirred solution of 24A (306.4 mg, 1.34 mmol) in MeOH was added ammoniumacetate (1.04 g, 13.43 mmol). NaBH₄ (83.81 mg, 2.22 mmol) was thenslowly added to prevent major exotherm. The reaction mixture was stirredfor 2 hours at RT followed by addition of NaOH (1M) and DCM. The organiclayer was washed with brine, dried, and concentrated under reducedpressure. The material was purified by silica gel chromatography usingEA and hexanes as eluent to afford the title compound.

Synthesis of 2,6-difluoro-4-(2-hydroxypropyl)benzoic acid (24C): To astirred solution of 24B (87.3 mg, 0.38 mmol) in THF was added LiOH(79.56 mg, 1.9 mmol). The reaction mixture was stirred at RT for 3 hoursthen HCl (1M) and EA was added. The organic layer was washed with brine,dried, and concentrated under reduced pressure to give the titlecompound which was used without further purification.

(2S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-(2-hydroxypropyl)benzamido)propanoic acid (24): The title compound was prepared accordingto the method presented for the synthesis of compound 16A and 16starting with 1E and 24C. MS (m/z) 550.2 [M+H]+. 1H NMR (400 MHz,DMSO-d6) δ 9.18 (d, J=8.1 Hz, 1H), 8.84 (dd, J=4.2, 1.6 Hz, 1H), 8.64(dd, J=8.6, 1.6 Hz, 1H), 8.16 (d, J=1.6 Hz, 1H), 7.90 (dd, J=7.9, 1.6Hz, 1H), 7.68-7.59 (m, 3H), 7.57 (d, J=7.9 Hz, 1H), 6.94 (d, J=8.8 Hz,2H), 4.80-4.69 (m, 1H), 3.80 (pd, J=8.9, 7.6, 3.0 Hz, 2H), 3.40 (s, 1H),2.62 (d, J=6.2 Hz, 2H), 1.02 (d, J=6.1 Hz, 3H).

Example 25

Synthesis of tert-butyl(S)-4-((3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-1-methoxy-1-oxopropan-2-yl)carbamoyl)-3,5-difluorobenzoate(25A): The title compound was prepared according to the method presentedfor the synthesis of compound 16A starting with4-(tert-butoxycarbonyl)-2,6-difluorobenzoic acid and 1E.

Synthesis of(S)-4-((3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-1-methoxy-1-oxopropan-2-yl)carbamoyl)-3,5-difluorobenzoicacid (25B): To a stirred solution of 25A (150 mg, 0.25 mmol) in DCM wasadded TFA (1.5 mL). The reaction mixture was stirred for 2 hours at RT,concentrated under reduced pressure, and then purified by silica gelchromatography using DCM and MeOH as the eluent to afford the titlecompound.

(S)-4-((1-carboxy-2-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)ethyl)carbamoyl)-3,5-difluorobenzoicacid (25): The title compound was prepared according to the methodpresented for the synthesis of compound 1 starting with 25B. MS (m/z)535.8 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.40 (d, J=8.2 Hz, 1H), 8.84(dd, J=4.1, 1.6 Hz, 1H), 8.64 (dd, J=8.7, 1.7 Hz, 1H), 8.16 (d, J=1.6Hz, 1H), 7.95-7.86 (m, 1H), 7.64 (t, J=4.3 Hz, 1H), 7.61 (d, J=5.1 Hz,1H), 7.57 (dd, J=7.7, 6.0 Hz, 2H), 4.80 (t, J=11.5 Hz, 1H), 3.79 (s,1H), 3.41 (s, 1H).

Example 26

(S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-(phenylcarbamoyl)benzamido)propanoic acid (26): The title compound was prepared accordingto the method presented for the synthesis of compound 16A and 16starting with 25B and aniline. MS (m/z) 611.2 [M+H]+. 1H NMR (400 MHz,DMSO-d6) δ 10.35 (s, 1H), 9.41 (d, J=8.3 Hz, 1H), 8.88-8.80 (m, 1H),8.65 (d, J=8.7 Hz, 1H), 8.16 (d, J=1.6 Hz, 1H), 7.91 (d, J=8.2 Hz, 1H),7.76-7.61 (m, 7H), 7.57 (d, J=7.9 Hz, 1H), 7.42-7.29 (m, 2H), 7.12 (t,J=7.4 Hz, 1H), 4.81 (s, 1H), 3.76 (s, 1H), 3.25-3.17 (m, 1H).

Example 27

Synthesis of methyl(R)-2,6-difluoro-4-((1-phenylethyl)carbamoyl)benzoate (27A): To astirred solution of 3,5-difluoro-4-(methoxycarbonyl)benzoic acid (20 mg,0.093 mmol) in DMF was added (R)-1-phenylethan-1-amine (13.46 mg, 0.11mmol), HATU (42 mg, 0.11 mmol), and TEA (0.06 mL, 0.463 mmol). Thereaction was stirred for 1 h at RT, concentrated under reduced pressure,and then purified by silica gel chromatography using DCM/MeOH as eluent.

Synthesis of (R)-2,6-difluoro-4-((1-phenylethyl)carbamoyl)benzoic acid(27B): To a stirred solution of 27A (29.5 mg, 0.09 mmol) in THF wasadded aqueous LiOH (0.46 mL, 1 M). The mixture was allowed to stir at RTfor 3 hours, concentrated under reduced pressure, and then purified bysilica gel chromatography using DCM/MeOH as eluent

(S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-(((R)-1-phenylethyl)carbamoyl)benzamido)propanoic acid (27): The title compound was preparedaccording to the method presented for the synthesis of compound 16A and16 starting with 27B. MS (m/z) 639.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ9.35 (d, J=8.3 Hz, 1H), 8.98 (d, J=7.9 Hz, 1H), 8.84 (dd, J=4.1, 1.6 Hz,1H), 8.64 (d, J=7.7 Hz, 1H), 8.16 (d, J=1.6 Hz, 1H), 7.90 (d, J=7.7 Hz,1H), 7.66-7.53 (m, 6H), 7.32 (dt, J=15.1, 7.5 Hz, 4H), 7.21 (t, J=7.1Hz, 1H), 5.11 (t, J=7.3 Hz, 1H), 4.80 (s, 1H), 3.50-3.40 (m, 1H), 1.45(d, J=7.0 Hz, 3H).

Example 28

(S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-((2,2,2-trifluoroethyl)carbamoyl)benzamido)propanoic acid (28): The title compound wasprepared according to the method presented for the synthesis of compound16A and 16 starting with 25B. MS (m/z) 616.9 [M+H]+. 1H NMR (400 MHz,DMSO-d6) δ 9.38 (d, J=8.3 Hz, 1H), 9.29 (t, J=6.4 Hz, 1H), 8.84 (dd,J=4.2, 1.6 Hz, 1H), 8.68-8.60 (m, 1H), 8.16 (d, J=1.6 Hz, 1H), 7.90 (d,J=8.1 Hz, 1H), 7.64 (d, J=4.6 Hz, 1H), 7.62-7.58 (m, 3H), 7.57 (d, J=7.9Hz, 1H), 4.80 (s, 1H), 4.09 (dd, J=9.8, 6.4 Hz, 1H), 3.75-3.60 (m, 1H).

Example 29

Synthesis of ethyl(S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-dichloro-4-iodobenzamido)propanoate(29A): The title compound was prepared according to the method presentedfor the synthesis of compound 16A starting with2,6-dichloro-4-iodobenzoic acid and 1E.

Synthesis of methyl(S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-dichloro-4-(3-hydroxy-3-methylbut-1-yn-1-yl)benzamido)propanoate(29B): To a stirred solution of 29A (60 mg, 0.09 mmol) in THF was added2-methylbut-3-yn-2-ol (0.02 ml, 0.27 mmol), CuI (3.44 mg, 0.02 mmol),PdCl₂(PPh₃)₂ (12.71 mg, 0.02 mmol), and DIEA (0.08 ml, 0.45 mmol). Thereaction mixture was allowed to stir for 1 h at 60° C. then concentratedunder reduced pressure and used without further purification.

(S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-dichloro-4-(3-hydroxy-3-methylbut-1-yn-1-yl)benzamido)propanoicacid (29): The title compound was prepared according to the methodpresented for the synthesis of compound 1 starting with 29B. MS (m/z)606.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 13.04 (s, 1H), 9.30 (d, J=7.9Hz, 1H), 8.83 (dd, J=4.1, 1.6 Hz, 1H), 8.64 (dd, J=8.6, 1.7 Hz, 1H),8.18-8.13 (m, 1H), 7.91 (d, J=8.2 Hz, 1H), 7.68-7.57 (m, 2H), 7.61-7.48(m, 1H), 7.43 (s, 1H), 7.41-7.30 (m, 3H), 4.85 (s, 1H), 3.76 (dd,J=14.4, 4.2 Hz, 1H), 3.39 (t, J=12.4 Hz, 1H), 1.43 (d, J=3.7 Hz, 6H).

Example 30

Synthesis of methyl quinoline-5-carboxylate (30A): To a stirred solutionof 3-nitrobenzoic acid (244.0 g, 1.46 mol) in conc. H₂SO₄ (750 mL) wasadded glycerol (1.17 L, 15.33 mol) and 3-aminobenzoic acid (500.0 g,3.65 mol). The resulting reaction mixture was heated to 150° C. for 7 h.Then the reaction mixture was cooled to 0° C. and treated with methanol(5.0 L) and the resulting reaction mixture was heated to reflux for 12h. The reaction mixture was cooled to 0° C. and quenched with ice waterand neutralized with solid Na₂CO₃. The aqueous was extracted with EA (4L×2), the organic layer was separated dried over Na₂SO₄ and concentratedunder reduced pressure. The material was purified by columnchromatography using EA/petroleum ether to obtain 30A.

Synthesis of 5-(methoxycarbonyl)quinoline 1-oxide (30C): m-CPBA (604.8g, 2.19 mol) was added to a solution of compound 30A (205.0 g, 1.095mol) in chloroform (4.1 L) at 0° C. The resulting reaction mixture wasallowed to warm RT and stirred for 6 h. The reaction mixture was cooledto 0° C. and quenched with sat NaHCO₃ solution and extracted with DCM.The organic layer was separated, dried over Na₂SO₄ and concentratedunder reduced pressure. The compound was purified by columnchromatography using 5% MeOH/DCM as eluent to obtain 30C.

Synthesis of 5-(methoxycarbonyl)-3-nitroquinoline 1-oxide (30D): t-BuONO(708.1 mL, 5.9 mol) was added to a solution of compound 30C (120.0 g,0.59 mol) in acetonitrile (6.0 L) at RT and the resulting reactionmixture was heated to 100° C. in an autoclave for 8 h. The reactionmixture was cooled to RT and concentrated under reduced pressure. Thecompound was washed with EA to afford compound 30D.

Synthesis of methyl 3-aminoquinoline-5-carboxylate (30E): Fe Powder(39.38 g, 0.705 mol) and conc. HCl (50.0 mL) were added to a solution ofcompound 30D (25.0 g, 0.1 mol) in a mixture of ethanol (500 mL) andwater (500 mL) at 70° C. and the resulting reaction mixture was stirredfor 18 h. The reaction mixture was cooled to RT, filtered throughcelite, concentrated under reduced pressure and extracted with DCM. Theorganic layer was separated, dried over Na₂SO₄ and concentrated undervacuum. The compound was purified by column chromatography using 50% EAin pet ether as eluent to obtain 30E.

Synthesis of methyl 3-fluoroquinoline-5-carboxylate (30F): A solution ofsodium nitrite (13.64 g, 0.197 mol) in water (60.0 mL) was added to asolution of compound 30E (20.0 g, 0.0989 mol) in 50% HBF₄ (200 mL) at 0°C. The reaction mixture was allowed warm to RT and stirred for 2 h, thenfiltered under vacuum. The filtered compound was added to chlorobenzene,and the reaction mixture was refluxed at 125° C. for 2 h. Thechlorobenzene was removed by distillation resulting in a material whichwas dissolved in DCM and water. The organic layer was washed with waterand brine, dried over Na₂SO₄ and concentrated under vacuum. The compoundwas purified by column chromatography using 4-5% EA in petroleum etheras eluent to obtain 30F.

Synthesis of methyl 8-bromo-3-fluoroquinoline-5-carboxylate (30G): NBS(41.89 g, 0.243 mol) was added to a stirred solution of 30F (25.0 g,0.121 mol) in H₂SO₄ (500.0 mL) at 0° C. and the resulting reactionmixture was allowed warm to RT and allowed to stir for 24 h. Thereaction mixture was poured onto crushed ice and the solid obtained wasfiltered and dried under reduced pressure to afford compound 30G.

Synthesis of (8-bromo-3-fluoroquinolin-5-yl)methanol (31H): To a stirredsolution of 30G (26.0 g, 0.091 mol) in THF (260 mL) was slowly added 2MLiBH₄ in THF (137 mL, 0.274 mol) at 0° C. The reaction mixture washeated to 40° C. for 2 h then cooled to 0° C., quenched with ice waterand stirred for 30 minutes. The reaction mixture was acidified with aq.2N HCl (pH 4-5) and heated to 40° C. for 2 h. The reaction mixture wascooled to RT and basified with sat. NaHCO₃ solution (pH 8-9), extractedwith DCM (250 mL×2). The organic layer was separated, dried over Na₂SO₄,and concentrated under reduced pressure. The compound was washed withpentane to afford 31H.

Synthesis of 8-bromo-5-(bromomethyl)-3-fluoroquinoline (301): PBr₃ (48.5g, 0.179 mol) was added to a stirred solution of 31H (23.0 g, 0.0897mol) in DCM (230 mL) at 0° C., the mixture was allowed warm to RT andallowed to stir for 18 h. The reaction mixture was concentrated, cooledto 0° C. and basified with sat. Na₂CO₃ solution (PH 8-9) to obtain asolid that was collected by filtration and dried under vacuum to obtain301.

Synthesis of methyl(S)-3-(8-bromo-3-fluoroquinolin-5-yl)-2-((diphenylmethylene)amino)propanoate (30J): To a stirred solution of methyl2-((diphenylmethylene)amino)acetate (16.6 g, 0.0655 mol) in DCM (500 mL)was added (−)-cinchonidine (1.93 g, 0.0065 mol) at RT. The reactionmixture was cooled to 0° C. KOH solution (50%) (133 mL) and 301 (23.0 g,0.0721) were added and the reaction mixture was allowed to stir at RTfor 6 h. The reaction mixture was diluted with water (200 mL) andstirred for 15 minutes. After washing with water and EA, the combinedorganic layer was dried over anhydrous Na₂SO₄, filtered through Celite,washed with EA, and concentrated under reduced pressure to obtain 30J.

Synthesis of free base methyl(S)-2-amino-3-(8-bromo-3-fluoroquinolin-5-yl) propanoate (30K): 4M HClin 1,4-dioxane (720 mL) was added to a stirred solution of 30J (60 g,0.1221 mol) in methanol (420 mL) at 0° C. The reaction mixture wasallowed to stir at RT for 36 h. The reaction mixture was concentratedunder reduced pressure, dissolved in water (100 mL) and washed with EA(100 mL×2 L). The aqueous layer was separated and basified (pH-8) usingSat.Na₂CO₃ and extracted with DCM (500 mL×5). The combined organiclayers were dried over anhydrous Na₂SO₄ and concentrated under reducedpressure to afford 30K.

Chiral purification of methyl(S)-2-amino-3-(8-bromo-3-fluoroquinolin-5-yl) propanoate hydrochloride(30K): 30K was enriched in the desired enantiomer by supercritical fluidchromatography using 50% (0.5% TEA in IPA) co-solvent, at a flow rate of100 mL/min, using an Chiralpak IC (30×250 mm), 5 μm column.

Synthesis of methyl(S)-2-amino-3-(8-bromo-3-fluoroquinolin-5-yl)propanoate hydrochloride(30K): The free amine was dissolved in DCM (300 mL) and treated with 4MHCl in 1,4-dioxane (100 mL) at 0° C. and the reaction mixture wasallowed to stir at RT for 30 min then concentrated under reducedpressure to afford 30K as the HCl salt.

Synthesis of methyl(S)-3-(8-bromo-3-fluoroquinolin-5-yl)-2-(2,6-dichlorobenzamido)propanoate (30L): The title compound was prepared according tothe method presented for the synthesis of compound 1F starting with 30Kand 2,6-dichlorobenzoyl chloride.

Synthesis of(S)-3-(8-(2-chloro-4-cyanophenyl)-3-fluoroquinolin-5-yl)-2-(2,6-dichlorobenzamido)propanoicacid (30): The title compound was prepared according to the methodpresented for the synthesis of compound 3B and 3 starting with 30L. MS(m/z) 542.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.24 (d, J=8.4 Hz, 1H),8.90 (d, J=2.7 Hz, 1H), 8.46 (d, J=10.3 Hz, 1H), 8.16 (dd, J=1.6, 0.4Hz, 1H), 7.92 (d, J=7.9 Hz, 1H), 7.73 (d, J=7.4 Hz, 1H), 7.62 (d, J=7.3Hz, 1H), 7.53 (d, J=7.9 Hz, 1H), 7.43-7.24 (m, 3H), 4.87 (s, 1H), 3.69(dd, J=14.6, 4.2 Hz, 1H), 3.45-3.35 (m, 1H).

Example 31

Synthesis of 5-bromo-8-iodo-2-methylquinoline (31A): To a stirredsolution of 2-iodo-5-bromoaniline (5 g, 17 mmol) in nitrobenzene (1.7mL) and 75% H₂SO₄ (15 mL) was added but-2-enal (2.35 g, 34 mmol) at RTand then slowly heated to 150° C. for 3 h. Caution: highly exothermicreaction. The mixture was cooled to RT and poured into ice-water whilemaintaining the temperature below 10° C. The pH was adjusted to ˜12 withsolid KOH, and the resulting material was collected. The material waswashed three times with water, then were taken up in ethyl acetate andfiltered. The organic solution was concentrated, then purified via flashchromatography, eluting with a linear gradient of 5-100% DCM/hexanes, toyield 31A.

Synthesis of5-bromo-8-(4-(ethoxymethyl)-2,6-dimethoxyphenyl)-2-methylquinoline(31B): To a stirred solution of compound 31A (850 mg, 2.44 mmol) and(4-(ethoxymethyl)-2,6-dimethoxyphenyl)boronic acid (586 mg, 2.44 mmol)in 1,2-dimethoxyethane (12 mL) was added 2M sodium carbonate in water(2.44 mL, 4.9 mmol), and the reaction was degassed with dry nitrogen. Tothis, tetrakis(triphenylphosphine)palladium(0) (141 mg, 0.12 mmol) wasadded, the reaction was sealed, and it was heated to 80° C. for 16hours. The reaction mixture was cooled to RT, diluted with ethylacetate, and washed with water and brine. It was then dried overanhydrous sodium sulfate, filtered, concentrated and purified via flashchromatography, eluting with a linear gradient of 5-50% ethylacetate/hexanes, to yield 31B.

Synthesis of methyl2-((tert-butoxycarbonyl)amino)-3-(8-(4-(ethoxymethyl)-2,6-dimethoxyphenyl)-2-methylquinolin-5-yl)acrylate(31C): To a stirred solution of 31B (190 mg, 0.46 mmol) in DMF (4.7 mL)was added palladium(II) acetate, and the reaction was degassed withnitrogen for 30 minutes. To this, methyl2-((tert-butoxycarbonyl)amino)acrylate (230 mg, 1.1 mmol),tetrabutylammonium chloride (152 mg, 0.55 mmol), and trimethylamine(0.074 mL, 0.53 mmol) were added, and the reaction was sealed and heatedto 90° C. for 3 hours. It was cooled to RT, diluted with ethyl acetate,and washed with 10% citric acid, saturated sodium bicarbonate, andsaturated sodium chloride. It was dried over anhydrous sodium sulfate,filtered, and concentrated. It was purified via flash chromatography,eluting with a linear gradient of 5-100% ethyl acetate/hexanes, to yieldcompound 31C.

Synthesis of methyl2-((tert-butoxycarbonyl)amino)-3-(8-(4-(ethoxymethyl)-2,6-dimethoxyphenyl)-2-methylquinolin-5-yl)propanoate(31D): To a stirred solution of 31C (150 mg, 0.28 mmol) and tosylhydrazide (781 mg, 4 mmol) in THF (3 mL) at 60° C. was added sodiumacetate (609 mg, 4 mmol) in water (3 mL) dropwise, then the reaction washeated to reflux overnight. It was partitioned between ethyl acetate andwater, and then the aqueous layer was extracted twice with ethylacetate. The combined organics were washed with saturated sodiumchloride, dried over anhydrous sodium sulfate, filtered, andconcentrated. The residue was twice more subjected to these conditionsto yield 31D.

Synthesis of methyl2-amino-3-(8-(4-(ethoxymethyl)-2,6-dimethoxyphenyl)-2-methylquinolin-5-yl)propanoate dihydrochloride (31E): To a stirred solution ofcompound 31D (150 mg, 0.28 mmol) in ethyl acetate (2 mL) was added 4Mhydrogen chloride in dioxane (0.7 mL, 1.8 mmol), and the reaction wasallowed to stir overnight at RT. It was diluted with EA, and theresulting solids were collected by trituration to yield 31E.

Synthesis of methyl2-(2,6-difluorobenzamido)-3-(8-(4-(ethoxymethyl)-2,6-dimethoxyphenyl)-2-methylquinolin-5-yl)propanoate (31F): The title compound wasprepared according to the method presented for the synthesis of compound1F starting with 31E and 2,6-difluorobenzoyl chloride.

Synthesis of2-(2,6-difluorobenzamido)-3-(8-(4-(ethoxymethyl)-2,6-dimethoxyphenyl)-2-methylquinolin-5-yl)propanoicacid (31G): Synthesized via sodium hydroxide method to yield 31G.

Synthesis of(S)-2-(2,6-difluorobenzamido)-3-(8-(4-(ethoxymethyl)-2,6-dimethoxyphenyl)-2-methylquinolin-5-yl)propanoic acid (31):2-(2,6-difluorobenzamido)-3-(8-(4-(ethoxymethyl)-2,6-dimethoxyphenyl)-2-methylquinolin-5-yl)propanoic acid (31G)was separated into its two enantiomers by supercritical fluidchromatography using 20% MeOH/DEA co-solvent on an IC SFC column toyield the desired enantiomer 31H as the second eluting peak. MS (m/z)565.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.56 (d, J=8.7 Hz, 1H),7.51-7.41 (m, 1H), 7.38 (d, J=7.4 Hz, 1H), 7.32 (d, J=8.7 Hz, 1H), 7.26(d, J=7.3 Hz, 1H), 7.15-7.05 (m, 2H), 6.68 (s, 2H), 4.50 (s, 2H), 4.40(s, 1H), 3.68-3.49 (m, 9H), 3.42-3.34 (m, 1H), 2.45 (s, 3H), 1.20 (t,J=7.0 Hz, 3H).

Example 32

Synthesis of (8-bromo-3-fluoroquinolin-5-yl)methanol (32A): A flaskcontaining methyl 8-bromo-3-fluoroquinoline-5-carboxylate (1.06 g, 3.73mmol) in THF (19 mL) was flushed with N₂, and then LiBH₄ (813 mg, 37.3mmol) was added in one portion. After stirring at RT for 1 h, thereaction mixture was cooled to 0° C. and water (6 mL) was added,followed by the dropwise addition of 1M HCl (84 mL). The reactionmixture was heated to 40° C. for 2.5 hours and then cooled to RT beforediluting with water and EA. Aqueous was extracted and the organic layerwas dried over anhydrous MgSO₄ and concentrated under reduced pressure.The material was purified by silica gel chromatography using 0-100% EAin hexanes to afford the title compound.

Synthesis of 8-bromo-5-(bromomethyl)-3-fluoroquinoline (32B):Triphenylphosphine (1.12 g, 4.27 mmol) and CBr₄ (1.42 g, 4.27 mmol) wereadded to a stirred solution of 32A (729 mg, 2.85 mmol) in DCM (5.7 mL)and this was stirred at RT for 20 min. The reaction mixture was thensubjected to silica gel chromatography using 0-40% EA in hexanes to givethe title compound.

Synthesis of tert-butyl(S)-3-(8-bromo-3-fluoroquinolin-5-yl)-2-((diphenylmethylene)amino)propanoate (32C): To a stirred solution of tert-butyl2-((diphenylmethylene)amino)acetate (270 mg, 0.914 mmol) in DCM (7 mL)was added (−)-cinchonidine (27 mg, 0.091 mmol). The mixture was cooledto 0° C. with an ice bath before adding 50% aq KOH solution (1.8 mL),followed by 32B (321 mg, 1.01 mmol). The reaction stirred in the icebath as it slowly warmed to RT. After 3.5 hours, the reaction wasdiluted with water and DCM, and aqueous was extracted. The organic layerwas dried over MgSO₄ and concentrated under reduced pressure. Thematerial was purified by silica gel chromatography using 0-30% EA inhexanes to afford the title compound.

Synthesis of tert-butyl(S)-3-(8-(2,6-dichloro-4-fluorophenyl)-3-fluoroquinolin-5-yl)-2-((diphenylmethylene)amino)propanoate(32D): 32C (65 mg, 0.122 mmol), (2,6-dichloro-4-fluorophenyl)boronicacid (51 mg, 0.244 mmol), K₃PO₄ (91 mg, 0.426 mmol), SPhos Pd G3 (95 mg,0.122 mmol) were dissolved in toluene (2.4 mL) and heated to 100° C. for3 hours. After cooling to RT, the reaction mixture was diluted with EAand filtered through celite. The filtrate was concentrate under reducedpressure and the resulting residue was purified by silica gelchromatography using 0-50% EA in hexanes to give the title compound.

Synthesis of tert-butyl(S)-2-amino-3-(8-(2,6-dichloro-4-fluorophenyl)-3-fluoroquinolin-5-yl)propanoate (32E): 2M HCl (0.43 mmol, 0.21 mL) was added toa stirred solution of 32D (88.2 mg, 0.14 mmol) in THF (0.84 mL). Afterstirring at RT for 2 hours, sat. NaHCO₃ and EA were added. Aqueous wasextracted and the organic layer was dried over MgSO₄ and concentratedunder reduced pressure. The material was purified by silica gelchromatography using 0-90% EA in hexanes with 1% TEA to afford the titlecompound.

Synthesis of tert-butyl(S)-3-(8-(2,6-dichloro-4-fluorophenyl)-3-fluoroquinolin-5-yl)-2-(2,6-difluorobenzamido)propanoate(32F): To a stirred solution of 32E (36.6 mg, 0.081 mmol) in DCM (0.54mL) was added TEA (23 μL, 0.161 mmol). The reaction was cooled to 0° C.before adding 2,6-difluorobenzoyl chloride (15 μL, 0.121 mmol) dropwise.After stirring at RT for 1.25 hours, water and DCM were added. Aqueouslayer was extracted and the organic layer was dried over MgSO₄ andconcentrated under reduced pressure. The material was purified by silicagel chromatography using 0-40% EA in hexanes to give the title compound.

Synthesis of(S)-3-(8-(2,6-dichloro-4-fluorophenyl)-3-fluoroquinolin-5-yl)-2-(2,6-difluorobenzamido)propanoicacid (32): TFA (0.12 mL, 1.61 mmol) was added to a stirred solution of32F (47.9 mg, 0.081 mmol) in DCM (0.40 mL). After stirring at RT for 3hours, more TFA (0.06 mL, 0.81 mmol) was added. The reaction was stirredfor another hour at RT, and then concentrated under reduced pressured.The material was purified by prep HPLC using 0-100% MeCN in water with1% TFA to afford the title compound. MS (m/z) 537.0 [M+H]+. 1H NMR (400MHz, DMSO-d6) δ 13.04 (s, 1H), 9.27 (d, J=8.2 Hz, 1H), 8.90 (d, J=2.7Hz, 1H), 8.45 (dd, J=10.5, 2.8 Hz, 1H), 7.70 (d, J=7.4 Hz, 1H), 7.65 (d,J=8.6 Hz, 2H), 7.59 (d, J=7.3 Hz, 1H), 7.48 (ddd, J=8.5, 6.5, 1.9 Hz,1H), 7.15-7.05 (m, 2H), 4.82 (ddd, J=10.2, 8.1, 4.5 Hz, 1H), 3.78-3.55(m, 1H), 3.43 (dd, J=14.7, 10.3 Hz, 1H).

Example 33

Synthesis of methyl(S)-2-(4-acetyl-2,6-difluorobenzamido)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)propanoate (33A): The title compound was preparedaccording to the method presented for the synthesis of compound 16Astarting with 1E and 4-acetyl-2,6-difluorobenzoic acid.

(2S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-(1-hydroxyethyl)benzamido)propanoic acid (33): The title compound was prepared accordingto the method presented for the synthesis of compound 24B and 16starting with 33A. MS (m/z) 563.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ9.19 (d, J=8.2 Hz, 1H), 8.83 (dd, J=4.2, 1.6 Hz, 1H), 8.63 (dd, J=8.7,1.6 Hz, 1H), 8.16 (dd, J=1.6, 0.4 Hz, 1H), 7.90 (d, J=7.6 Hz, 1H),7.73-7.50 (m, 4H), 7.03 (d, J=8.8 Hz, 2H), 4.71 (d, J=6.5 Hz, 1H), 1.27(d, J=6.5 Hz, 3H).

Example 34

Synthesis of 8-bromo-7-fluoro-5-methylquinoline (34A): the titlecompound was prepared according to the method presented for thesynthesis of compound 1A in Example 1 starting with2-bromo-3-fluoro-5-methylaniline. MS (m/z) 240.0 [M+H]⁺.

Synthesis of 8-bromo-5-(bromomethyl)-7-fluoroquinoline 34B: the titlecompound was prepared according to the method presented for thesynthesis of compound 1B in Example 1 starting with 34A. MS (m/z) 317.9[M+H]⁺.

Synthesis of8-bromo-7-fluoro-5-(((2S,5S)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2-yl)methyl)quinoline (34C): A solution of(R)-2-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (0.365 mL, 2.04 mmol)in THF (10 mL) was cooled to −78° C. with stirring and under positivenitrogen pressure. The mixture was treated dropwise with n-BuLi (0.98mL, 1.6 M, 1.57 mmol). A solution of 34B (497 mg, 1.57 mmol) is thenadded as a THF solution (1.0 M). After 30 minutes, the reaction mixturewas removed from the cooling bath, quenched with a saturated aqueoussolution of NH₄Cl, and allowed to warm to RT with vigorous stirring. Theresulting mixture was extracted twice with EA, and the combined organiclayers were concentrated under reduced pressure. The residue waspurified by silica gel chromatography using 0-20% EA in hexanes toafford the title compound. MS (m/z) 422.1 [M+H]⁺.

Synthesis of methyl(S)-2-amino-3-(8-bromo-7-fluoroquinolin-5-yl)propanoate dihydrochloride(34D): To a stirred solution of 34C (380 mg, 0.9 mmol) in THF (3.6 mL)was added 2M aqueous hydrochloric acid (2.7 mL, 5.4 mmol). After 3 h,the reaction mixture was concentrated under reduced pressure to affordthe title compound (as a mixture with valine methyl esterhydrochloride), which was advanced without further purification. MS(m/z) 327.0 [M+H]⁺.

Synthesis of Methyl(S)-3-(8-bromo-7-fluoroquinolin-5-yl)-2-(2,6-difluorobenzamido)propanoate (34E): the title compound was prepared according to themethod presented for the synthesis of compound 1F in Example 1 startingwith 34. MS (m/z) 467.0 [M+H]⁺.

Synthesis of(2S)-3-(8-(2-chloro-4-cyanophenyl)-7-fluoroquinolin-5-yl)-2-(2,6-difluorobenzamido)propanoicacid (34): the title compound was prepared according to the methodpresented for the synthesis of compound 3B and 3 starting with 34E. MS(m/z) 510.1 [M+H]⁺. 1H NMR (400 MHz, DMSO-d6) δ 9.27 (dd, J=8.3, 1.3 Hz,1H), 8.87 (dt, J=3.9, 1.8 Hz, 1H), 8.67 (dd, J=8.6, 1.6 Hz, 1H), 8.24(t, J=1.9 Hz, 1H), 7.95 (ddd, J=7.9, 4.2, 1.7 Hz, 1H), 7.67-7.57 (m,3H), 7.49 (ttd, J=8.7, 6.6, 2.3 Hz, 1H), 7.16-7.08 (m, 2H), 4.82 (dddd,J=10.8, 8.4, 4.2, 2.2 Hz, 1H), 3.85 (ddd, J=18.1, 14.5, 4.1 Hz, 1H),3.42 (ddd, J=19.5, 14.6, 10.8 Hz, 1H).

Example 35

Synthesis of(S)-(5-(2-(2,6-dichlorobenzamido)-3-methoxy-3-oxopropyl)-3-fluoroquinolin-8-yl)boronicacid (35A): the title compound was prepared according to the methodpresented for the synthesis of compound 5A starting with 30L.

Synthesis of(S)-2-(2,6-dichlorobenzamido)-3-(3-fluoro-8-(4-(trifluoromethyl)isoquinolin-3-yl)quinolin-5-yl)propanoic acid (35): the title compoundwas prepared according to the method presented for the synthesis ofcompound 4C and 4 starting with 35A and3-bromo-4-(trifluoromethyl)isoquinoline (71B). MS (m/z) 601.9 [M+H]⁺. 1HNMR (400 MHz, DMSO-d6) δ 9.60 (d, J=3.4 Hz, 1H), 9.29 (dd, J=14.2, 8.4Hz, 1H), 8.81 (dd, J=3.4, 2.8 Hz, 1H), 8.46 (ddd, J=10.1, 6.9, 2.8 Hz,1H), 8.38 (dd, J=8.2, 1.1 Hz, 1H), 8.18 (d, J=8.6 Hz, 1H), 8.10-8.01 (m,1H), 7.94-7.85 (m, 1H), 7.74 (d, J=7.4 Hz, 1H), 7.69 (dd, J=7.3, 1.9 Hz,1H), 7.45-7.35 (m, 3H), 4.85 (dtd, J=23.5, 9.2, 4.5 Hz, 1H), 3.69 (dt,J=14.4, 4.4 Hz, 1H), 3.44 (dd, J=14.6, 10.1 Hz, 1H).

Example 36

Synthesis of methyl(S)-3-(8-bromo-3-iodoquinolin-5-yl)-2-(2,6-difluorobenzamido) propanoate(36A): A solution of 3A (300 mg, 0.67 mmol) in AcOH (2.5 mL) was treatedwith N-iodosuccinimide (300 mg, 1.34 mmol) and stirred at 70° C. for 24h. A second quantity of N-iodosuccinimide (300 mg, 1.34 mmol) was added,and stirring continued at 70° C. for an additional 24 h. The mixture wascooled to RT and concentrated under reduced pressure. The resultingresidue was dissolved in DCM, and washed with saturated aqueous NaHCO₃,back-extracting the aqueous twice with DCM. The combined organic layerswere adsorbed onto silica gel for purification by silica gelchromatography using 0-100% EA in hexanes to afford the title compound.MS (m/z) 575.0 [M+H]+.

Synthesis of methyl(S)-3-(8-bromo-3-cyanoquinolin-5-yl)-2-(2,6-difluorobenzamido)propanoate (36B): A suspension of 36A (50 mg, 0.087 mmol) and cuprouscyanide (12 mg, 0.130 mmol) in DMF (1.5 mL) was stirred at 135° C. undermicrowave irradiation for 30 min. The reaction mixture was then cooledto RT, diluted with EA and saturated aqueous NaCl, and filtered throughcelite. The phases were separated, and the aqueous layer was furtherextracted twice with EA. The combined organic layers were concentratedunder reduced pressure and the resulting residue purified by silica gelchromatography using 0-40% EA in hexanes to afford the title compound.MS (m/z) 474.0 [M+H]+.

Synthesis of(S)-3-(3-cyano-8-(4-(ethoxymethyl)-2,6-dimethoxyphenyl)quinolin-5-yl)-2-(2,6-difluorobenzamido)propanoicacid (36): the title compound was prepared according to the methodpresented for the synthesis of compound 18 starting with 36B. MS (m/z)576.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.27 (d, J=8.1 Hz, 1H), 9.21(d, J=2.1 Hz, 1H), 9.02 (d, J=2.0 Hz, 1H), 7.69 (d, J=7.4 Hz, 1H), 7.63(d, J=7.4 Hz, 1H), 7.49 (tt, J=8.4, 6.6 Hz, 1H), 7.15-7.08 (m, 2H), 6.71(q, J=1.3 Hz, 2H), 4.82 (ddd, J=10.0, 8.2, 4.5 Hz, 1H), 4.52 (s, 2H),3.77-3.70 (m, 1H), 3.61-3.45 (m, 9H), 1.21 (t, J=7.0 Hz, 3H).

Example 37

Synthesis of methyl(S)-3-(8-bromo-3-(trifluoromethyl)quinolin-5-yl)-2-(2,6-difluorobenzamido)propanoate (37A): A vial was charged with 36A (50 mg, 0.087mmol) and (1,10-phenanthroline)(trifluoromethyl)copper(I) (98 mg, 0.313mmol), sealed with a septum cap, and purged with nitrogen for 15 min.DMF (1 mL, previously degassed by sparging with nitrogen for 15 min) wasadded, and the mixture stirred vigorously at 50° C. for 1 h. Thereaction mixture was cooled to RT, diluted with EA, and filtered throughcelite. The resulting filtrate was washed with saturated aqueous NaHCO₃,and the aqueous layer back-extracted twice with EA. The combined organiclayers were adsorbed onto silica gel for silica gel chromatography using0-50% EA in hexanes to afford the title compound. MS (m/z) 517.1 [M+H]+.

Synthesis of(S)-2-(2,6-difluorobenzamido)-3-(8-(4-(ethoxymethyl)-2,6-dimethoxyphenyl)-3-(trifluoromethyl)quinolin-5-yl)propanoic acid (37): the titlecompound was prepared according to the method presented for thesynthesis of compound 18 starting with 37A. MS (m/z) 619.2 [M+H]+. 1HNMR (400 MHz, DMSO-d6) δ 9.31 (d, J=8.0 Hz, 1H), 9.08-9.06 (m, 1H), 8.97(dd, J=2.3, 1.1 Hz, 1H), 7.70 (d, J=7.5 Hz, 1H), 7.63 (d, J=7.3 Hz, 1H),7.50 (tt, J=8.5, 6.6 Hz, 1H), 7.15-7.08 (m, 2H), 6.72 (q, J=1.3 Hz, 2H),4.78 (ddd, J=9.7, 8.0, 4.6 Hz, 1H), 4.53 (s, 2H), 3.77 (dd, J=14.8, 4.6Hz, 1H), 3.61-3.43 (m, 9H), 1.22 (t, J=7.0 Hz, 3H).

Example 38

Synthesis of4-((2-bromo-5-methylphenyl)amino)-1,1,1-trifluorobut-3-en-2-one (38A):To a stirred solution of 2-bromo-5-methylaniline (2.149 g, 12 mmol) and4-(tert-butylamino)-1,1,1-trifluorobut-3-en-2-one (2.05 g, 10.5 mmol) inglacial acetic acid (4 mL) was added TFA (4 mL), and the reaction washeated to 75° C. for 16 hours. It was cooled to RT, poured onto water,and the solids were collected via filtration to yield 38A.

Synthesis of 8-bromo-5-methyl-2-(trifluoromethyl)quinoline (38B): To astirred suspension of compound 38A (2.81 g, 9.1 mmol) in heptane (9 mL)was added POCl₃ (0.855 mL, 9.12 mmol), and the reaction was heated to100° C. overnight. It was poured onto a solution of 2M sodium carbonatein water. It was extracted twice with ethyl acetate, and the combinedorganics were washed with saturated sodium chloride solution, dried overanhydrous sodium sulfate, filtered, and concentrated. It was purifiedvia flash chromatography, eluting with a linear gradient of 1-20% ethylacetate/hexanes, to yield 38B.

Synthesis of 8-bromo-5-(bromomethyl)-2-(trifluoromethyl)quinoline (38C):To a stirred solution of 38B (1.32 g, 4.6 mmol) in benzene (10 mL) wasadded N-bromosuccinimide (0.97 g, 5.5 mmol), and the reaction was heatedto reflux under a tungsten work lamp for 16 hours. It was cooled to RT,filtered and concentrated. The residue was dissolved in ethyl acetateand washed twice with water and once with saturated sodium chloridesolution. It was purified via flash chromatography, eluting with alinear gradient of 5-70% DCM/hexanes, to yield compound 38C.

Synthesis of tert-butyl3-(8-bromo-2-(trifluoromethyl)quinolin-5-yl)-2-((diphenylmethylene)amino)propanoate (38D): A stirred solution of tert-butyl2-((diphenylmethylene) amino)acetate (260 mg, 0.88 mmol) intetrahydrofuran (3 mL) under dry nitrogen was cooled to −78° C. 1MLithium hexamethyldisilazide in THF (0.968 mL, 0.968 mmol) was addeddropwise, then the reaction was stirred at this temperature for 15minutes. To this, a solution of 38C (357 mg, 0.97 mmol) in THF (2 mL)was added, and the reaction was allowed to warm to RT and stir for 16hours. It was quenched by the addition of saturated ammonium chloride,and it was partitioned between water and ethyl acetate. The aqueous wasextracted with ethyl acetate, and the combined organics were washed withsaturated sodium chloride, dried over anhydrous sodium sulfate,filtered, and concentrated. It was purified via flash chromatography,eluting with a linear gradient of 5-50% ethyl acetate/hexanes, to yieldcompound 38D.

Synthesis of tert-butyl2-amino-3-(8-bromo-2-(trifluoromethyl)quinolin-5-yl)propanoate (38E): Toa stirred solution of compound 38D (335 mg, 0.57 mmol) intetrahydrofuran (6 mL) was added 0.5M citric acid in water (5.7 mL, 2.87mmol), and the reaction was allowed to stir for 1 h at RT. It wasdiluted with water, and washed once with diethyl ether. The aqueous wastreated with 1M sodium hydroxide in water until a pH of ˜8 was reached,and it was extracted twice with diethyl ether. The combined extractswere washed with saturated sodium chloride solution, dried overanhydrous magnesium sulfate, filtered, and concentrated to yield 38E.

Synthesis of tert-butyl3-(8-bromo-2-(trifluoromethyl)quinolin-5-yl)-2-(2,6-difluorobenzamido)propanoate(38F): The title compound was prepared according to the method presentedfor the synthesis of compound 1F starting with 38E and2,6-difluorobenzoyl chloride.

Synthesis of tert-butyl2-(2,6-difluorobenzamido)-3-(8-(4-(ethoxymethyl)-2,6-dimethoxyphenyl)-2-(trifluoromethyl)quinolin-5-yl)propanoate(38G): To a solution of 38F (187 mg, 0.33 mmol) and(4-(ethoxymethyl)-2,6-dimethoxyphenyl)boronic acid (104 mg, 0.44 mmol)in 1,2-dimethoxyethane (3 mL) was added 2M sodium carbonate in water(0.5 mL, 0.67 mmol), and the reaction was degassed with nitrogen. Tothis, XPhos Pd G3 (14 mg, 0.017 mmol) was added, the reaction wassealed, and it was heated to 85° C. for 1 h. It was cooled to RT andpurified by flash chromatography, eluting with a linear gradient of1-10% MeOH/DCM, to yield 38G.

Synthesis of2-(2,6-difluorobenzamido)-3-(8-(4-(ethoxymethyl)-2,6-dimethoxyphenyl)-2-(trifluoromethyl)quinolin-5-yl)propanoic acid (38): To asolution of 38G (214 mg, 0.32 mmol) in DCM (1 mL) was added TFA (723 mg,6 mmol), and the reaction was allowed to stir at RT for 4 hours. It wasconcentrated and purified via preparatory HPLC to yield 38. MS (m/z)619.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.30 (d, J=8.1 Hz, 1H), 8.85(dd, J=8.9, 0.8 Hz, 1H), 7.95 (d, J=8.8 Hz, 1H), 7.68 (d, J=7.5 Hz, 1H),7.61 (d, J=7.3 Hz, 1H), 7.48 (tt, J=8.4, 6.5 Hz, 1H), 7.11 (dd, J=8.5,7.5 Hz, 2H), 6.72 (q, J=1.3 Hz, 2H), 4.77 (ddd, J=10.1, 8.0, 4.5 Hz,1H), 4.52 (d, J=0.7 Hz, 2H), 3.76 (dd, J=14.7, 4.5 Hz, 1H), 3.64-3.50(m, 8H), 3.44 (dd, J=14.8, 10.1 Hz, 1H), 1.20 (t, J=7.0 Hz, 3H).

Example 39

Synthesis of 8-bromo-6-fluoro-5-methylquinoline (39A) the title compoundwas prepared according to the method presented for the synthesis ofcompound 1A in Example 1 using 2-bromo-4-fluoro-5-methylaniline. MS(m/z) 240.0 [M+H]+.

Synthesis of 8-bromo-5-(bromomethyl)-6-fluoroquinoline (39B): the titlecompound was prepared according to the method presented for thesynthesis of compound 1B in Example 1 using 39A. MS (m/z) 317.9 [M+H]+.

Synthesis of8-bromo-6-fluoro-5-(((2S,5S)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2-yl)methyl)quinoline (39C): the title compound was preparedaccording to the method presented for the synthesis of compound 34C4using 39B. MS (m/z) 422.1 [M+H]+.

Synthesis of Methyl(S)-2-amino-3-(8-bromo-6-fluoroquinolin-5-yl)propanoate (39D): the titlecompound was prepared according to the method presented for thesynthesis of compound 34 using 39C. MS (m/z) 327.0 [M+H]+.

Synthesis of Methyl(S)-3-(8-bromo-6-fluoroquinolin-5-yl)-2-(2,6-difluorobenzamido)propanoate (39E): the title compound was prepared according to themethod presented for the synthesis of compound 16A in Example 16 using39D. MS (m/z) 467.0 [M+H]+.

Synthesis of(S)-2-(2,6-difluorobenzamido)-3-(8-(4-(ethoxymethyl)-2,6-dimethoxyphenyl)-6-fluoroquinolin-5-yl)propanoic acid (39): the title compoundwas prepared according to the method presented for the synthesis ofcompound 18 using 39E. MS (m/z) 569.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6)δ 9.30 (d, J=8.3 Hz, 1H), 8.83-8.70 (m, 2H), 7.68 (dd, J=8.8, 4.3 Hz,1H), 7.55-7.44 (m, 2H), 7.11 (dd, J=8.5, 7.6 Hz, 2H), 6.75 (s, 2H), 4.77(td, J=8.5, 6.2 Hz, 1H), 4.54 (s, 2H), 3.70-3.50 (m, 11H), 1.22 (t,J=7.0 Hz, 3H).

Example 40

(S)-2-(2,6-difluorobenzamido)-3-(8-(4-(ethoxymethyl)-2,6-dimethoxyphenyl)-7-fluoroquinolin-5-yl)propanoicacid (40): the title compound was prepared according to the methodpresented for the synthesis of compound 18 using 34E. MS (m/z) 569.2[M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.32 (d, J=8.1 Hz, 1H), 8.83 (dd,J=4.3, 1.5 Hz, 1H), 8.70 (d, J=5.0 Hz, 1H), 7.64 (dd, J=8.0, 3.9 Hz,1H), 7.56-7.46 (m, 2H), 7.18-7.10 (m, 2H), 6.75 (d, J=1.7 Hz, 2H), 4.80(ddd, J=10.6, 8.1, 4.1 Hz, 1H), 4.54 (s, 2H), 3.80 (dd, J=14.6, 4.1 Hz,1H), 3.62-3.55 (m, 8H), 3.43 (dd, J=14.8, 10.5 Hz, 1H), 1.22 (t, J=7.0Hz, 3H).

Example 41

Synthesis of 2,6-difluoro-4-((phenoxycarbonyl)amino)benzoic acid (41A):To a stirred solution of 4-amino-2,6-difluorobenzoic acid (504 mg, 2.16mmol) in DCM was added phenyl chloroformate (0.41 ml, 3.24 mmol) andpyridine (0.87 ml, 10.81 mmol). The reaction mixture was allowed to stirfor 3 hr at RT. The reaction mixture was concentrated under reducedpressure and purified by reverse phase preparative chromatography usingaqueous 0.1% TFA/MeCN as the eluent.

Synthesis of(S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-((phenoxycarbonyl)amino)benzamido)propanoicacid (41): The title compound was prepared according to the methodpresented for the synthesis of compound 16A and 16 starting with 41A and1E. MS (m/z) 686.5 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 13.04 (s, 1H),10.76 (s, 1H), 9.18 (d, J=8.0 Hz, 1H), 8.81 (s, 1H), 7.85-7.37 (m, 6H),7.32-7.13 (m, 5H), 6.72 (s, 2H), 4.74 (s, 1H), 4.52 (s, 2H), 3.85-3.75(m, 1H), 3.60-3.51 (m, 8H), 1.20 (t, J=7.0 Hz, 3H).

Example 42 and Example 43

Synthesis of methyl (S)-3-(8-bromoquinolin-5-yl)-2-(4-cyano-2,6-difluorobenzamido) propanoate (42A): To a stirred solution of4-cyano-2,6-difluorobenzoic acid (0.12 g, 0.65 mmol) in DCM was added 1D(0.2 g, 0.65 mmol), HATU (0.25 g, 0.65 mmol) and TEA (1 mL). Thereaction mixture was allowed to stir ON at RT. The reaction mixture wasconcentrated under reduced pressure and purified by silica gelchromatography using EA in hexanes as the eluent.

(S)-2-(4-cyano-2,6-difluorobenzamido)-3-(8-(4-(ethoxymethyl)-2,6-dimethoxyphenyl)quinolin-5-yl)propanoic acid (42): To a microwave vial was added42A (0.24 g, 0.5 mmol), (4-(ethoxymethyl)-2,6-dimethoxyphenyl)boronicacid (200 mg, 0.5 mmol), XPhos Pd G3 (0.043 g, 0.05 mmol), and K₃PO₄(0.21 g, 0.15 mmol) in dioxane (2 mL). The reaction mixture was allowedto stir at 120° C. for 30 min. EA and water was added to the reactionmixture. The organic layer was washed with brine, dried over anhydrousNa₂SO₄, and concentrated under reduced pressure. The mixture waspurified by silica gel chromatography using MeOH and DCM as eluent toafford both 42 and 43. MS (m/z) 576.2 [M+H]⁺. 1H NMR (400 MHz, DMSO-d6)δ 8.72 (dd, J=4.1, 1.6 Hz, 1H), 8.60 (s, 1H), 8.15 (s, 1H), 7.72 (s,1H), 7.57 (d, J=8.1 Hz, 2H), 7.53-7.46 (m, 2H), 7.36 (d, J=7.3 Hz, 1H),6.68 (d, J=2.3 Hz, 2H), 4.61 (s, 1H), 4.50 (s, 2H), 3.68 (dd, J=14.0,4.7 Hz, 1H), 3.56 (d, J=7.0 Hz, 1H), 3.52 (d, J=7.1 Hz, 6H), 3.44-3.33(m, 1H), 1.20 (t, J=7.0 Hz, 3H).

(S)-2-(4-carbamoyl-2,6-difluorobenzamido)-3-(8-(4-(ethoxymethyl)-2,6-dimethoxyphenyl)quinolin-5-yl)propanoic acid (43). MS (m/z) 595.5 [M+H]⁺. 1H NMR(400 MHz, DMSO-d6) δ 13.15 (s, 1H), 9.48 (d, J=8.0 Hz, 1H), 8.74 (dd,J=4.1, 1.7 Hz, 1H), 8.53 (dd, J=8.7, 1.7 Hz, 1H), 8.01-7.73 (m, 2H),7.53 (dd, J=8.6, 4.1 Hz, 1H), 7.48 (d, J=7.4 Hz, 1H), 7.38 (d, J=7.3 Hz,1H), 6.76-6.63 (m, 2H), 4.75 (td, J=8.8, 4.4 Hz, 1H), 4.50 (s, 2H),3.91-3.61 (m, 1H), 3.55 (t, J=7.0 Hz, 2H), 3.53 (s, 3H), 3.46-3.22 (m,4H), 1.20 (t, J=7.0 Hz, 3H).

Example 44

Synthesis of methyl(S)-2-amino-3-(8-(4-(ethoxymethyl)-2,6-dimethoxyphenyl)quinolin-5-yl)propanoate (44A): The title compound was preparedaccording to the method presented for the synthesis of compound 1Estarting with (4-(ethoxymethyl)-2,6-dimethoxy phenyl)boronic acid.

(S)-2-(4-amino-2,6-difluorobenzamido)-3-(8-(4-(ethoxymethyl)-2,6-dimethoxyphenyl)quinolin-5-yl)propanoic acid (44): The title compound was preparedaccording to the method presented for the synthesis of compound 16A and16 starting with 44A and 4-amino-2,6-difluorobenzoic acid. MS (m/z)567.6 [M+H]⁺. 1H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 2H), 8.67 (d, J=7.9Hz, 1H), 7.64 (t, J=37.5 Hz, 3H), 6.74 (d, J=2.2 Hz, 2H), 6.11 (d,J=10.7 Hz, 2H), 4.75-4.62 (m, 1H), 4.53 (s, 2H), 3.81-3.65 (m, 1H), 3.58(d, J=7.0 Hz, 2H), 3.55 (d, J=6.1 Hz, 7H), 1.20 (t, J=7.0 Hz, 3H).

Example 45

Synthesis of methyl 2,6-difluoro-4-(methylsulfonamido)benzoate (45A): Toa stirred solution of methyl 4-amino-2,6-difluorobenzoate (500 mg, 0.3mmol) in DCM was added methyl sulfonyl chloride (0.31 ml, 0.4 mmol), andpyridine (1.08 mL, 1.3 mmol). The reaction was stirred for at RT ON. Thereaction mixture was diluted with EA, washed with 1M HCl, bicarbonate,brine, and dried, filtered, and concentrated. The material wasrecrystallized from EA/hexanes to yield the title compound.

Synthesis of 2,6-difluoro-4-(methylsulfonamido)benzoic acid (45B): To astirred solution of 45A (534 mg, 0.2 mmol) in THF was added aqueous LiOH(5 mL, 2 M). The mixture was allowed to stir at RT for 2 days, dilutedwith water and acidified with 1 M HCl. The material was extracted withDCM, dried, filtered, and concentrated under reduced pressure. Thematerial purified by silica gel chromatography using EA/hexanes aseluent to afford the title compound.

(S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-(methylsulfonamido)benzamido)propanoic acid (45): The title compound wasprepared according to the method presented for the synthesis of compound16A and 16 starting with 45B. MS (m/z) 585.1 [M+H]+. 1H NMR (400 MHz,DMSO-d6) δ 10.46 (s, 1H), 9.15 (d, J=8.1 Hz, 1H), 8.85 (dd, J=4.1, 1.6Hz, 1H), 8.65 (dd, J=8.7, 1.7 Hz, 1H), 8.17 (dd, J=1.6, 0.4 Hz, 1H),7.92 (dd, J=7.9, 1.6 Hz, 1H), 7.70-7.55 (m, 4H), 6.83 (d, J=9.3 Hz, 2H),4.83-4.68 (m, 1H), 3.87-3.66 (m, 1H), 3.51-3.33 (m, 1H), 3.14 (s, 3H).

Example 46

(S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-(phenylsulfonamido)benzamido)propanoic acid (46): The title compound wasprepared according to the method presented for the synthesis ofcompounds 45A, 45B, and 45 starting with phenyl sulfonyl chloride. MS(m/z) 647.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 9.12 (d,J=8.1 Hz, 1H), 8.84 (dd, J=4.2, 1.6 Hz, 1H), 8.63-8.60 (m, 1H), 8.17 (d,J=1.7 Hz, 1H), 7.92 (dd, J=7.9, 1.7 Hz, 1H), 7.89-7.82 (m, 2H),7.73-7.53 (m, 7H), 6.75 (d, J=9.2 Hz, 2H), 4.75-4.65 (m, 1H), 3.82-3.65(m, 1H), 3.47-3.27 (m, 1H).

Example 47

Synthesis methyl(S)-3-(8-bromoquinolin-5-yl)-2-(2,6-difluoro-4-((4-(2-fluoropyridin-4-yl)phenyl)sulfonamido)benzamido)propanoate(47A): The title compound was prepared according to the method presentedfor the synthesis of compound 16 of Example 16 starting with2,6-difluoro-4-((4-(2-fluoropyridin-4-yl)phenyl)sulfonamido)benzoicacid.

Synthesis of(S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-((4-(2-fluoropyridin-4-yl)phenyl)sulfonamido)benzamido)propanoicacid (47): The title compound was prepared according to the methodpresented for the synthesis of compound 3B and 3 starting with 47A. MS(m/z) 742.4 [M+H]⁺. 1H NMR (400 MHz, DMSO-d6) δ 11.21 (s, 1H), 9.11 (d,J=8.1 Hz, 1H), 8.81 (dd, J=4.1, 1.6 Hz, 1H), 8.59 (dd, J=8.6, 1.7 Hz,1H), 8.33 (d, J=5.3 Hz, 1H), 8.14 (d, J=1.6 Hz, 1H), 8.09-8.03 (m, 2H),8.01-7.94 (m, 2H), 7.89 (dd, J=7.9, 1.6 Hz, 1H), 7.72 (dt, J=5.4, 1.8Hz, 1H), 7.64-7.51 (m, 5H), 6.78 (d, J=9.2 Hz, 2H), 4.83-4.59 (m, 1H),3.71 (s, 1H), 3.34 (s, 1H).

Example 48

Synthesis of 2,6-difluoro-4-((methylsulfonyl)methyl)benzoic acid (48A):To a stirred solution of methyl 4-(bromomethyl)-2,6-difluorobenzoate(125 mg, 0.47 mmol) in DMF was added methyl sodium sulfinate (96.28 mg,0.94 mmol). This was heated to 65° C. and stirred for 1 h. EA and waterwere added. The combined organics were washed with brine, dried, andconcentrated. The material was then converted to the title compoundaccording to the method presented for the synthesis of compound 1G.

(S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-((methylsulfonyl)methyl)benzamido)propanoic acid (48): The title compound was preparedaccording to the method presented for the synthesis of compound 16A and16 starting with 48A. MS (m/z) 584.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ9.30 (d, J=8.2 Hz, 1H), 8.84 (dd, J=4.2, 1.6 Hz, 1H), 8.65 (dd, J=8.7,1.6 Hz, 1H), 8.15 (d, J=1.6 Hz, 1H), 7.90 (dd, J=7.9, 1.7 Hz, 1H),7.68-7.53 (m, 4H), 7.16 (d, J=8.1 Hz, 2H), 4.84-4.73 (m, 1H), 4.55 (s,2H), 3.77 (s, 1H), 3.40 (s, 1H), 2.93 (s, 3H).

Example 49

(S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-((phenylsulfonyl)methyl)benzamido)propanoic acid (49): The title compound was preparedaccording to the method presented for the synthesis of compound 48A ofExample 48 starting with phenyl sodium sulfinate, followed by the methodpresented for 16 and 16C starting with 49A. MS (m/z) 646.3 [M+H]+. 1HNMR (400 MHz, DMSO-d6) δ 9.28 (d, J=8.2 Hz, 1H), 8.83 (dd, J=4.1, 1.6Hz, 1H), 8.64 (dd, J=8.7, 1.7 Hz, 1H), 8.15 (d, J=1.6 Hz, 1H), 7.90 (dd,J=7.9, 1.7 Hz, 1H), 7.81-7.69 (m, 3H), 7.69-7.50 (m, 6H), 6.88 (d, J=8.1Hz, 2H), 4.82-4.73 (m, 1H), 4.77 (s, 2H), 3.76 (s, 1H), 3.40 (s, 1H).

Example 50

(S)-2-(2,6-difluoro-4-((4-(2-fluoropyridin-4-yl)phenyl)sulfonamido)benzamido)-3-(8-(4-(ethoxymethyl)-2,6-dimethoxyphenyl)quinolin-5-yl)propanoicacid (50): The title compound was prepared according to the methodpresented for the synthesis of compound 3B and 3 starting with 47A and(4-(ethoxymethyl)-2,6-dimethoxyphenyl)boronic acid. MS (m/z) 802.4[M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 11.24 (s, 1H), 9.16 (d, J=8.0 Hz,1H), 8.83 (s, 2H), 8.35 (d, J=5.3 Hz, 1H), 8.12-8.04 (m, 2H), 8.03-7.95(m, 2H), 7.82-7.43 (m, 5H), 6.81 (d, J=9.0 Hz, 2H), 6.74 (s, 2H), 4.72(q, J=8.3 Hz, 1H), 4.54 (s, 2H), 3.73 (dd, J=13.3, 3.5 Hz, 1H), 3.59 (d,J=7.0 Hz, 1H), 3.54 (d, J=2.0 Hz, 6H), 3.43 (s, 1H), 1.22 (t, J=7.0 Hz,3H).

Example 51

(S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-((methylsulfonyl)methyl)benzamido)propanoic acid (51): The title compound was preparedaccording to the method presented for the synthesis of compound 3B and 3starting with 47A and (2,3-dihydrobenzo[b][1,4]dioxin-5-yl)boronic acid.MS (m/z) 741.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 11.21 (s, 1H), 9.12(d, J=8.1 Hz, 1H), 8.87 (s, 1H), 8.71 (s, 1H), 8.38-8.26 (m, 1H),8.10-8.02 (m, 2H), 8.02-7.93 (m, 2H), 7.78-7.47 (m, 5H), 6.90 (d, J=9.3Hz, 2H), 6.79 (t, J=8.8 Hz, 2H), 4.67 (s, 1H), 4.20 (s, 2H), 4.05 (s,2H), 3.71 (d, J=14.0 Hz, 1H), 3.42-3.27 (m, 1H).

Example 52

(S)-2-(2,6-difluoro-4-((4-(2-fluoropyridin-4-yl)phenyl)sulfonamido)benzamido)-3-(8-(thiophen-3-yl)quinolin-5-yl)propanoicacid (52): The title compound was prepared according to the methodpresented for the synthesis of compound 3B and 3 starting with 47A andthiophen-3-ylboronic acid. MS (m/z) 689.2 [M+H]+. 1H NMR (400 MHz,DMSO-d6) δ 11.23 (s, 1H), 9.11 (d, J=8.1 Hz, 1H), 8.97 (dd, J=4.1, 1.7Hz, 1H), 8.60 (dd, J=8.6, 1.7 Hz, 1H), 8.37-8.32 (m, 1H), 8.09-8.04 (m,3H), 8.01-7.96 (m, 2H), 7.86 (d, J=7.5 Hz, 1H), 7.74 (dt, J=5.4, 1.8 Hz,1H), 7.69-7.59 (m, 4H), 7.51 (d, J=7.5 Hz, 1H), 6.81 (d, J=9.1 Hz, 2H),4.66 (ddd, J=10.1, 8.1, 4.4 Hz, 1H), 3.69 (dd, J=14.3, 4.4 Hz, 1H), 3.31(dd, J=14.5, 10.1 Hz, 1H).

Example 53

Synthesis of(S)-3-(8-boronoquinolin-5-yl)-2-(2,6-difluoro-4-((4-(2-fluoropyridin-4-yl)phenyl)sulfonamido)benzamido)propanoicacid (53A): The title compound was prepared according to the methodpresented for the synthesis of compound 4B starting with 47A.

(S)-3-(8-(2-chloro-4-(cyanomethyl)phenyl)quinolin-5-yl)-2-(2,6-difluoro-4-((4-(2-fluoropyridin-4-yl)phenyl)sulfonamido)benzamido)propanoicacid (53): The title compound was prepared according to the methodpresented for the synthesis of compound 5B and 5 starting with 53A and2-(4-bromo-3-chlorophenyl)acetonitrile. MS (m/z) 756.1 [M+H]+. 1H NMR(400 MHz, DMSO-d6) δ 11.19 (s, 1H), 9.10 (d, J=8.1 Hz, 1H), 8.81 (dd,J=4.1, 1.6 Hz, 1H), 8.58 (dd, J=8.7, 1.7 Hz, 1H), 8.33 (dt, J=5.3, 0.6Hz, 1H), 8.09-8.02 (m, 2H), 8.01-7.94 (m, 2H), 7.72 (dt, J=5.4, 1.8 Hz,1H), 7.62-7.49 (m, 5H), 7.43-7.32 (m, 2H), 6.79 (d, J=9.1 Hz, 2H), 4.67(d, J=11.2 Hz, 1H), 4.14 (s, 2H), 3.36 (s, 2H).

Example 54

(S)-3-(8-(2-chloro-4-cyclopropylphenyl)quinolin-5-yl)-2-(2,6-difluoro-4-((4-(2-fluoropyridin-4-yl)phenyl)sulfonamido)benzamido)propanoicacid (54): The title compound was prepared according to the methodpresented for the synthesis of compound 3B and 3 starting with 47A and(2-chloro-4-cyclopropylphenyl)boronic acid. MS (m/z) 757.2 [M+H]+. 1HNMR (400 MHz, DMSO-d6) δ 11.23 (s, 1H), 9.12 (d, J=8.1 Hz, 1H), 8.82 (d,J=4.3 Hz, 1H), 8.61 (d, J=8.7 Hz, 1H), 8.35 (d, J=5.3 Hz, 1H), 8.13-8.05(m, 2H), 8.03-7.95 (m, 2H), 7.74 (dt, J=5.3, 1.8 Hz, 1H), 7.66-7.52 (m,4H), 7.25 (d, J=1.8 Hz, 1H), 7.21 (d, J=7.9 Hz, 1H), 7.11 (dd, J=8.1,1.8 Hz, 1H), 6.80 (d, J=9.1 Hz, 2H), 4.76-4.64 (m, 1H), 3.82-3.62 (m,1H), 3.45-3.25 (m, 1H), 2.02 (tt, J=8.4, 5.1 Hz, 1H), 1.07-0.99 (m, 2H),0.84-0.73 (m, 2H).

Example 55

(S)-2-(2,6-difluoro-4-((4-(2-fluoropyridin-4-yl)phenyl)sulfonamido)benzamido)-3-(8-(3,5-dimethylisoxazol-4-yl)quinolin-5-yl)propanoicacid (55): The title compound was prepared according to the methodpresented for the synthesis of compound 3B and 3 starting with 47A and3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole.MS (m/z) 702.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 11.19 (s, 1H), 9.07(d, J=8.2 Hz, 1H), 8.88 (dd, J=4.1, 1.6 Hz, 1H), 8.58 (dd, J=8.7, 1.6Hz, 1H), 8.33 (d, J=5.3 Hz, 1H), 8.05 (s, 1H), 8.01-7.93 (m, 2H), 7.72(dt, J=5.4, 1.8 Hz, 1H), 7.65-7.57 (m, 3H), 7.52 (d, J=7.4 Hz, 1H), 6.77(d, J=9.1 Hz, 2H), 4.69 (s, 1H), 3.75-3.60 (m, 1H), 3.30 (dd, J=14.4,10.6 Hz, 1H), 2.22 (s, 3H), 2.01 (s, 3H).

Example 56

(S)-2-(2,6-difluoro-4-((4-(2-fluoropyridin-4-yl)phenyl)sulfonamido)benzamido)-3-(8-(pyrimidin-4-yl)quinolin-5-yl)propanoicacid (56): The title compound was prepared according to the methodpresented for the synthesis of compound 5B and 5 starting with 53A and4-bromopyrimidine. MS (m/z) 685.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ11.21 (s, 1H), 9.30 (d, J=1.4 Hz, 1H), 9.11 (d, J=8.2 Hz, 1H), 8.99 (dd,J=4.2, 1.6 Hz, 1H), 8.86 (d, J=5.4 Hz, 1H), 8.67 (dd, J=8.7, 1.7 Hz,1H), 8.42-8.25 (m, 2H), 8.19 (d, J=7.5 Hz, 1H), 8.10-8.00 (m, 2H),8.01-7.92 (m, 2H), 7.74-7.70 (m, 1H), 7.71-7.66 (m, 1H), 7.63 (d, J=7.6Hz, 1H), 7.59 (d, J=1.5 Hz, 1H), 6.78 (d, J=9.1 Hz, 2H), 4.68 (ddd,J=10.3, 8.2, 4.4 Hz, 1H), 3.81-3.65 (m, 1H), 3.34 (d, J=7.0 Hz, 1H).

Example 57

(S)-2-(2,6-difluoro-4-((4-(2-fluoropyridin-4-yl)phenyl)sulfonamido)benzamido)-3-(8-(5-(trifluoromethyl)pyridin-2-yl)quinolin-5-yl)propanoicacid (57): The title compound was prepared according to the methodpresented for the synthesis of compound 5B and 5 starting with 53A and2-bromo-5-(trifluoromethyl)pyridine. MS (m/z) 752.4 [M+H]+. 1H NMR (400MHz, DMSO-d6) δ 11.21 (s, 1H), 9.20-9.05 (m, 2H), 8.98 (dd, J=4.2, 1.6Hz, 1H), 8.69 (dd, J=8.7, 1.7 Hz, 1H), 8.38-8.23 (m, 3H), 8.11 (d, J=7.5Hz, 1H), 8.09-8.02 (m, 2H), 8.00-7.90 (m, 2H), 7.76-7.65 (m, 2H), 7.63(d, J=7.5 Hz, 1H), 7.58 (d, J=1.7 Hz, 1H), 6.78 (d, J=9.1 Hz, 2H),4.78-4.62 (m, 1H), 3.74 (dd, J=14.5, 4.4 Hz, 1H), 3.36 (dd, J=14.5, 10.2Hz, 1H).

Example 58

(S)-2-(2,6-difluoro-4-((4-(2-fluoropyridin-4-yl)phenyl)sulfonamido)benzamido)-3-(8-(pyrimidin-2-yl)quinolin-5-yl)propanoicacid (58): The title compound was prepared according to the methodpresented for the synthesis of compound 5B and 5 starting with 53A and2-bromopyrimidine. MS (m/z) 685.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ11.22 (s, 1H), 9.29 (d, J=4.9 Hz, 1H), 9.23 (d, J=8.7 Hz, 1H), 9.15-9.02(m, 3H), 8.76 (s, 1H), 8.33 (dd, J=5.3, 0.6 Hz, 1H), 8.10-8.00 (m, 2H),8.00-7.92 (m, 2H), 7.86 (d, J=7.7 Hz, 1H), 7.71 (dt, J=5.3, 1.8 Hz, 1H),7.67 (t, J=4.9 Hz, 1H), 7.58 (p, J=0.7 Hz, 1H), 6.76 (d, J=9.1 Hz, 2H),4.77 (ddd, J=10.4, 8.3, 4.4 Hz, 1H), 3.92-3.79 (m, 1H), 3.47 (dd,J=14.6, 10.4 Hz, 1H).

Example 59

(S)-3-(8-(2-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-((4-(2-fluoropyridin-4-yl)phenyl)sulfonamido)benzamido)propanoicacid (59): The title compound was prepared according to the methodpresented for the synthesis of compound 5B and 5 starting with 53A and2-bromobenzonitrile. MS (m/z) 708.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ11.22 (d, J=15.6 Hz, 1H), 9.23-9.03 (m, 1H), 8.90-8.77 (m, 1H),8.77-8.47 (m, 1H), 8.33 (dd, J=5.3, 2.2 Hz, 1H), 8.18-7.82 (m, 5H),7.82-7.15 (m, 7H), 6.89-6.72 (m, 2H), 4.78-4.36 (m, 1H), 3.72 (d, J=10.6Hz, 1H), 3.30 (m, 1H).

Example 60

(S)-2-(2,6-difluoro-4-((4-(2-fluoropyridin-4-yl)phenyl)sulfonamido)benzamido)-3-(8-(3-fluoro-2-methoxyphenyl)quinolin-5-yl)propanoicacid (60): The title compound was prepared according to the methodpresented for the synthesis of compound 3B and 3 starting with 47A and(3-fluoro-2-methoxyphenyl)boronic acid. MS (m/z) 731.2 [M+H]+. 1H NMR(400 MHz, DMSO-d6) δ 11.20 (s, 1H), 9.11 (d, J=8.1 Hz, 1H), 8.85 (dd,J=4.1, 1.6 Hz, 1H), 8.61 (d, J=8.6 Hz, 1H), 8.37-8.29 (m, 1H), 8.11-8.02(m, 2H), 8.02-7.93 (m, 2H), 7.72 (dt, J=5.3, 1.8 Hz, 1H), 7.65-7.50 (m,4H), 7.31 (ddd, J=11.8, 8.2, 1.6 Hz, 1H), 7.15 (td, J=8.0, 5.1 Hz, 1H),7.06-7.01 (m, 1H), 6.79 (d, J=9.1 Hz, 2H), 4.74-4.62 (m, 1H), 3.71 (dd,J=14.4, 4.4 Hz, 1H), 3.48 (d, J=1.4 Hz, 3H), 3.38-3.28 (m, 1H).

Example 61

(S)-2-(2,6-difluoro-4-((4-(2-fluoropyridin-4-yl)phenyl)sulfonamido)benzamido)-3-(8-(4-fluoro-2-(methylsulfonyl)phenyl)quinolin-5-yl)propanoicacid (61): The title compound was prepared according to the methodpresented for the synthesis of compound 3B and 3 starting with 47A and(4-fluoro-2-(methylsulfonyl)phenyl)boronic acid. MS (m/z) 779.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) (mixture of 50:50 diastereomers) δ 11.21 (s,1H), 9.12 (dd, J=8.1, 3.4 Hz, 1H), 8.80 (td, J=3.8, 3.3, 1.5 Hz, 1H),8.60 (t, J=7.4 Hz, 1H), 8.33 (d, J=5.3 Hz, 1H), 8.10-8.02 (m, 2H),8.01-7.94 (m, 2H), 7.87 (ddd, J=8.9, 2.8, 1.2 Hz, 1H), 7.73 (dd, J=5.3,1.7 Hz, 1H), 7.68-7.57 (m, 3H), 7.61-7.48 (m, 2H), 7.41-7.32 (m, 1H),6.79 (dd, J=9.1, 1.9 Hz, 2H), 4.76-4.61 (m, 1H), 3.77 (dd, J=14.3, 4.0Hz, 0.5H), 3.62 (dd, J=14.7, 5.1 Hz, 0.5H), 3.44 (dd, J=14.6, 9.6 Hz,0.5H), 3.27 (dd, J=14.5, 10.5 Hz, 0.5H), 2.85 (s, 1.5H), 2.80 (s, 1.5H).

Example 62

(S)-3-(8-(chroman-8-yl)quinolin-5-yl)-2-(2,6-difluoro-4-((4-(2-fluoropyridin-4-yl)phenyl)sulfonamido)benzamido)propanoic acid (62): The title compound wasprepared according to the method presented for the synthesis of compound3B and 3 starting with 47A and chroman-8-ylboronic acid. MS (m/z) 739.2[M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 11.22 (s, 1H), 9.12 (d, J=8.1 Hz,1H), 8.88 (s, 1H), 8.33 (dt, J=5.4, 0.6 Hz, 1H), 8.10-8.01 (m, 2H),8.01-7.90 (m, 2H), 7.72 (dt, J=5.4, 1.8 Hz, 1H), 7.59 (q, J=1.1 Hz, 3H),7.14 (d, J=7.8 Hz, 1H), 7.01 (d, J=7.3 Hz, 1H), 6.91 (t, J=7.4 Hz, 1H),6.86-6.64 (m, 2H), 4.75-4.57 (m, 1H), 3.97-3.85 (m, 2H), 3.72 (d, J=14.3Hz, 1H), 3.43-3.27 (m, 1H), 2.82 (t, J=6.5 Hz, 2H), 1.87 (t, J=5.6 Hz,3H).

Example 63

(S)-2-(2,6-difluoro-4-((4-(2-fluoropyridin-4-yl)phenyl)sulfonamido)benzamido)-3-(8-(o-tolyl)quinolin-5-yl)propanoicacid (63): The title compound was prepared according to the methodpresented for the synthesis of compound 3B and 3 starting with 47A ando-tolylboronic acid. MS (m/z) 697.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ11.20 (s, 1H), 9.09 (d, J=8.2 Hz, 1H), 8.81 (dd, J=4.2, 1.6 Hz, 1H),8.62 (d, J=8.7 Hz, 1H), 8.36-8.28 (m, 1H), 8.11-8.01 (m, 2H), 7.97 (d,J=8.4 Hz, 2H), 7.72 (dt, J=5.4, 1.8 Hz, 1H), 7.65-7.55 (m, 2H),7.55-7.41 (m, 2H), 7.34-7.17 (m, 3H), 7.13 (d, J=7.0 Hz, 1H), 6.78 (d,J=9.5 Hz, 2H), 4.70 (s, 1H), 3.72 (dd, J=14.4, 4.4 Hz, 1H), 3.32 (dd,J=14.4, 10.3 Hz, 1H), 1.87 (s, 3H).

Example 64

(2S)-2-(2,6-difluoro-4-((4-(2-fluoropyridin-4-yl)phenyl)sulfonamido)benzamido)-3-(8-(2-methoxy-6-methylphenyl)quinolin-5-yl)propanoicacid (64): The title compound was prepared according to the methodpresented for the synthesis of compound 3B and 3 starting with 47A and(2-methoxy-6-methylphenyl)boronic acid. MS (m/z) 727.5 [M+H]+. 1H NMR(400 MHz, DMSO-d6) δ 13.03 (s, 1H), 11.20 (s, 1H), 9.08 (d, J=8.2 Hz,1H), 8.73 (d, J=42.8 Hz, 2H), 8.33 (d, J=5.3 Hz, 1H), 8.13-7.89 (m, 4H),7.72 (dt, J=5.3, 1.7 Hz, 1H), 7.69-7.37 (m, 4H), 7.28 (t, J=7.9 Hz, 1H),6.90 (t, J=8.9 Hz, 2H), 6.83-6.71 (m, 2H), 4.79-4.66 (m, 1H), 3.77 (d,J=14.2 Hz, 1H), 3.49 (s, 3H), 3.28 (dd, J=14.4, 10.6 Hz, 1H), 1.74 (s,3H).

Example 65

(S)-2-(2,6-difluoro-4-((4-(2-fluoropyridin-4-yl)phenyl)sulfonamido)benzamido)-3-(8-(2-(trifluoromethyl)phenyl)quinolin-5-yl)propanoicacid (65): The title compound was prepared according to the methodpresented for the synthesis of compound 3B and 3 starting with 47A and(2-(trifluoromethyl)phenyl)boronic acid. MS (m/z) 751.5 [M+H]+. 1H NMR(400 MHz, DMSO-d6) δ 11.20 (d, J=2.3 Hz, 1H), 9.10 (dd, J=8.2, 6.2 Hz,1H), 8.77 (dt, J=4.0, 1.9 Hz, 1H), 8.59 (d, J=8.5 Hz, 1H), 8.33 (d,J=5.3 Hz, 1H), 8.10-8.02 (m, 2H), 8.01-7.93 (m, 2H), 7.82 (dt, J=7.9,1.9 Hz, 1H), 7.75-7.54 (m, 6H), 7.51 (d, J=1.9 Hz, 2H), 7.32 (dd, J=7.7,4.4 Hz, 1H), 6.78 (dd, J=9.0, 3.5 Hz, 2H), 4.69 (ddd, J=10.2, 8.1, 4.6Hz, 1H), 3.71 (ddd, J=29.9, 14.4, 4.4 Hz, 1H), 3.34 (ddd, J=25.9, 14.5,10.2 Hz, 1H).

Example 66

(S)-3-(8-(4-chloroisoquinolin-3-yl)quinolin-5-yl)-2-(2,6-difluorobenzamido)propanoicacid (66): The title compound was prepared according to the methodpresented for the synthesis of compound 5B and 5 starting with 5A and3-bromo-4-chloroisoquinoline. MS (m/z) 514.1 [M+H]+. 1H NMR (400 MHz,DMSO-d6) δ 9.30 (d, J=8.1 Hz, 1H), 8.88 (d, J=4.3 Hz, 1H), 8.77 (s, 1H),7.98 (s, 1H), 7.78 (dd, J=7.8, 1.5 Hz, 1H), 7.74 (d, J=7.3 Hz, 1H),7.70-7.56 (m, 3H), 7.49 (tt, J=8.4, 6.5 Hz, 1H), 7.35-7.27 (m, 1H),7.18-7.08 (m, 2H), 4.75 (td, J=9.5, 4.5 Hz, 1H), 3.77 (dd, J=14.5, 4.5Hz, 1H), 3.68 (s, 3H), 3.44 (dd, J=14.5, 9.9 Hz, 1H).

Example 67

(S)-2-(2,6-difluorobenzamido)-3-(4-methoxy-1-methyl-2-oxo-1,2-dihydro-[3,8′-biquinolin]-5′-yl)propanoicacid (67): The title compound was prepared according to the methodpresented for the synthesis of compound 11A and 11 starting with 5A and3-bromo-4-methoxy-1-methylquinolin-2(1H)-one. MS (m/z) 518.1 [M+H]+. 1HNMR (400 MHz, DMSO-d6) δ 9.41 (d, J=0.8 Hz, 1H), 9.31 (d, J=8.1 Hz, 1H),8.81 (dd, J=4.2, 1.6 Hz, 1H), 8.72 (dd, J=8.7, 1.7 Hz, 1H), 8.38-8.29(m, 1H), 8.24 (dq, J=8.5, 0.9 Hz, 1H), 8.02 (ddd, J=8.4, 6.9, 1.3 Hz,1H), 7.87 (ddd, J=8.1, 7.0, 1.1 Hz, 1H), 7.78 (d, J=7.3 Hz, 1H),7.72-7.64 (m, 2H), 7.48 (tt, J=8.5, 6.6 Hz, 1H), 7.16-7.07 (m, 2H), 4.80(ddd, J=10.1, 8.1, 4.4 Hz, 1H), 3.81 (dd, J=14.5, 4.4 Hz, 1H), 3.46 (dd,J=14.5, 10.1 Hz, 1H).

Example 68

(S)-2-(2,6-dichlorobenzamido)-3-(8-(6-methyl-3-(trifluoromethyl)pyridin-2-yl)quinolin-5-yl)propanoicacid (68): The title compound was prepared according to the methodpresented for the synthesis of compound 4C and 4 starting with 4B and2-chloro-6-methyl-3-(trifluoromethyl)pyridine. MS (m/z) 549.5 [M+H]+. 1HNMR (400 MHz, DMSO-d6) δ 9.31 (d, J=8.3 Hz, 1H), 8.81 (dd, J=4.2, 1.6Hz, 1H), 8.69 (dd, J=8.7, 1.7 Hz, 1H), 8.20 (d, J=8.3 Hz, 1H), 7.70-7.52(m, 4H), 7.48-7.35 (m, 3H), 4.84 (td, J=9.3, 4.3 Hz, 1H), 3.75 (dd,J=14.6, 4.4 Hz, 1H), 3.44 (dd, J=14.6, 10.1 Hz, 1H), 2.58 (s, 3H).

Example 69

(S)-2-(2,6-dichlorobenzamido)-3-(8-(6-methoxy-3-(trifluoromethyl)pyridin-2-yl)quinolin-5-yl)propanoicacid (69): The title compound was prepared according to the methodpresented for the synthesis of compound 4C and 4 starting with 4B and2-chloro-6-methoxy-3-(trifluoromethyl)pyridine. MS (m/z) 565.9 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 9.28 (s, 1H), 8.83 (dd, J=4.2, 1.6 Hz, 1H),8.68 (dd, J=8.7, 1.7 Hz, 1H), 8.16 (d, J=8.9 Hz, 1H), 7.70-7.58 (m, 3H),7.47-7.34 (m, 3H), 7.06 (dt, J=8.7, 0.8 Hz, 1H), 4.86 (m, 1H), 3.81 (s,3H), 3.78 (m, 1H), 3.43 (m, 1H).

Example 70

(S)-2-(2,6-difluorobenzamido)-3-(8-(5-methoxy-2-methyl-3-oxo-2,3-dihydropyridazin-4-yl)quinolin-5-yl)propanoicacid (70): The title compound was prepared according to the methodpresented for the synthesis of compound 11A and 11 starting with 5A and4-chloro-5-methoxy-2-methylpyridazin-3(2H)-one. MS (m/z) 495.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 9.30 (d, J=7.6 Hz, 1H), 8.88 (d, J=4.4 Hz,1H), 8.75 (d, J=8.6 Hz, 1H), 8.27 (s, 1H), 7.77-7.65 (m, 1H), 7.59 (d,J=7.8 Hz, 2H), 7.48 (tt, J=8.5, 6.6 Hz, 1H), 7.12 (dd, J=8.4, 7.6 Hz,2H), 4.74 (s, 1H), 3.86-3.63 (m, 7H), 3.43 (q, J=13.6 Hz, 1H).

Example 71

Synthesis of 4-(trifluoromethyl)isoquinolin-3-amine (71A): To a stirredsolution of 3-amino isoquinoline (150 mg, 1.04 mmol) in MeCN was added3,3-dimethyl-1-(trifluoromethyl)-1,2-benziodoxole (412.1 mg, 1.25 mmol)and tris(trimethylsilyl)silyl chloride (0.35 ml, 1.25 mmol). Thismixture was heated to 80° C. for 1 h. The reaction mixture was filteredthrough celite, rinsed with EA and purified by silica gel chromatographyusing EA in hexanes as eluent to give the title compound.

Synthesis of 3-bromo-4-(trifluoromethyl)isoquinoline (71B): To a stirredsolution of 71A (91 mg, 0.43 mmol) in HBr (6.9 mL) was added Br₂ (0.13ml, 2.57 mmol). The reaction mixture was kept at 0° C. for 10 minutes atwhich time NaNO₂ (147.96 mg, 2.14 mmol) was added as a premade solutionin water (5 mL). The reaction mixture was allowed to stir at 0° C. for30 min then allowed to warm to RT for 60 min. The reaction was quenchedwith sodium bicarbonate, extracted with DCM, concentrated and purifiedby silica gel chromatography eluting Hex/EA to give the title compound.

(S)-2-(2,6-difluorobenzamido)-3-(8-(4-(trifluoromethyl)isoquinolin-3-yl)quinolin-5-yl)propanoicacid (71): The title compound was prepared according to the methodpresented for the synthesis of compound 5B and 5 starting with 4B and71B. MS (m/z) 552.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.60 (d, J=3.3Hz, 1H), 9.29 (t, J=7.6 Hz, 1H), 8.75 (dt, J=3.9, 1.8 Hz, 1H), 8.65(ddd, J=8.7, 5.6, 1.7 Hz, 1H), 8.38 (d, J=8.2 Hz, 1H), 8.18 (d, J=8.7Hz, 1H), 8.05 (ddd, J=8.6, 6.9, 1.4 Hz, 1H), 7.90 (t, J=7.6 Hz, 1H),7.70 (dd, J=7.3, 4.7 Hz, 1H), 7.66-7.58 (m, 2H), 7.55-7.41 (m, 1H), 7.12(q, J=8.2 Hz, 2H), 4.77 (dtd, J=18.5, 8.8, 4.4 Hz, 1H), 3.77 (ddd,J=25.7, 14.5, 4.5 Hz, 1H), 3.49-3.34 (m, 1H).

Example 72

(S)-3-(8-(6-amino-3-(trifluoromethyl)pyridin-2-yl)quinolin-5-yl)-2-(2,6-dichlorobenzamido)propanoic acid (72): The title compound was prepared accordingto the method presented for the synthesis of compound 4C and 4 startingwith 4B and 6-chloro-5-(trifluoromethyl)pyridin-2-amine. MS (m/z) 550.4[M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.33 (d, J=8.3 Hz, 1H), 8.89 (dd,J=4.1, 1.6 Hz, 1H), 8.70 (dd, J=8.7, 1.6 Hz, 1H), 7.97 (d, J=9.1 Hz,1H), 7.74-7.63 (m, 3H), 7.49-7.36 (m, 3H), 6.81 (d, J=9.1 Hz, 1H), 4.80(td, J=9.2, 4.4 Hz, 1H), 3.74 (dd, J=14.5, 4.4 Hz, 1H), 3.43 (dd,J=14.6, 9.9 Hz, 1H).

Example 73

(S)-2-(2,6-dichlorobenzamido)-3-(8-(1,6-dimethyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)quinolin-5-yl)propanoicacid (73): The title compound was prepared according to the methodpresented for the synthesis of compound 11A and 11 starting with 4B and3-iodo-1,6-dimethyl-4-(trifluoromethyl)pyridin-2(1H)-one. MS (m/z) 578.1[M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 13.00 (s, 1H), 9.27 (dd, J=27.2, 8.3Hz, 1H), 8.83 (dt, J=4.2, 2.0 Hz, 1H), 8.69 (d, J=8.6 Hz, 1H), 7.72-7.59(m, 2H), 7.49-7.31 (m, 4H), 6.55 (d, J=4.7 Hz, 1H), 4.90-4.71 (m, 1H),3.73 (td, J=14.4, 4.0 Hz, 1H), 3.47 (d, J=4.2 Hz, 3H), 3.38 (ddd,J=24.5, 14.7, 10.5 Hz, 1H), 2.52 (m, 3H).

Example 74

Synthesis of tert-butyl 4-bromo-2,6-difluorobenzoate (74A): To a stirredsolution of 4-bromo-2,6-difluorobenzoic acid (5 g, 21.1 mmol) in DCM (50mL) and tert-butyl alcohol (50 mL) was added di-tert-butyl dicarbonate(9.2 g, 42.2 mol) followed by 4-dimethylaminopyridine (0.8 g, 6.3 mmol).The reaction mixture was allowed to stir at RT for 12 h. The reactionmixture was concentrated under reduced pressure, dissolved in ethylacetate (100 mL) and washed with a 10% aqueous solution of citric acid(100 mL). The organic layer was washed with brine, dried over anhydrousNa₂SO₄, and concentrated under reduced pressure to afford material. Thismaterial was suspended in hexanes, the solid was filtered off and thefiltrate was evaporated under reduced pressure to afford compound 74A.MS (m/z) 236.6 [M+H-C₄H₈]⁺. ¹H NMR (400 MHz, DMSO-d6) δ 7.69-7.56 (m,2H), 1.50 (s, 9H).

Synthesis of tert-butyl(R)-2,6-difluoro-4-((1,1,1-trifluorobutan-2-yl)amino)benzoate (74B): Toa stirred suspension of tert-butyl 4-bromo-2,6-difluorobenzoate (74A)(250 mg, 0.55 mmol), (R)-1,1,1-trifluorobutan-2-amine (85 mg, 0.67mmol), and cesium carbonate (904 mg, 2.8 mmol) in toluene (5 mL) wasadded XPhos Pd G3 (42 mg, 0.06 mmol). The reaction mixture was spargedwith nitrogen and then heated to 90° C. for 12 h. The mixture was cooledto RT and diluted with ethyl acetate (50 mL). The resultant suspensionwas filtered through a pad of celite, and the filtrate was evaporatedunder reduced pressure to afford compound 74B. MS (m/z) 284.1[M+H-C₄H₈]⁺.

Synthesis of(R)-2,6-difluoro-4-((1,1,1-trifluorobutan-2-yl)amino)benzoic acid (74C):To a stirred solution of tert-butyl(R)-2,6-difluoro-4-((1,1,1-trifluorobutan-2-yl)amino)benzoate (74B) (188mg, 0.55 mmol) in DCM (1 mL) was added TFA (1 mL). The reaction mixturewas allowed to stir at RT for 20 mins. The reaction mixture wasconcentrated under reduced pressure to afford material that was purifiedby silica gel column chromatography and eluted by ethyl acetate inhexane to afford compound 74C. MS (m/z) 338.1 [M+H]⁺.

(S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)propanoic acid (74): The title compound wasprepared according to the method presented for the synthesis of compound16A and 16 starting with 74C. MS (m/z) 617.2 [M+H]+. 1H NMR (400 MHz,DMSO-d6) δ 8.87-8.77 (m, 2H), 8.64 (dd, J=8.7, 1.7 Hz, 1H), 8.15 (dd,J=1.7, 0.4 Hz, 1H), 7.90 (dd, J=7.9, 1.7 Hz, 1H), 7.73-7.44 (m, 4H),6.76 (d, J=9.4 Hz, 1H), 6.43 (d, J=11.6 Hz, 2H), 4.68 (s, 1H), 4.29 (d,J=10.2 Hz, 1H), 3.73 (s, 1H), 3.49-3.33 (m, 1H), 1.75 (ddt, J=10.1, 7.5,3.8 Hz, 1H), 1.51 (ddt, J=17.6, 14.4, 7.3 Hz, 1H), 0.90 (t, J=7.3 Hz,3H).

Example 75

Synthesis of(R)-2,6-difluoro-4-(2-(trifluoromethyl)piperidin-1-yl)benzoic acid(75A): To a 150 mL pressure vessel containing a stir bar was addedmethyl 4-bromo-2,6-difluoro benzoate (700 mg, 1.8 mmol), RuPhos (169 mg,0.36 mmol), tBuBrettPhos Pd G3 (155 mg, 0.18 mmol), Cs₂CO₃ (2.95 g, 9.1mmol), (R)-2-(trifluoromethyl)piperidine (416 mg, 2.7 mmol) and toluene(18 mL). The reaction vessel was then sealed and heated at 90° C.overnight. The reaction mixture was cooled to RT and filtered over a padof Celite, rinsed with EA and the filtrate was evaporated to drynessunder reduced pressure. The material was purified by silica gelchromatography using EA in Hexane as eluent. To this material was addedTHF (6 mL) and aqueous LiOH (6.2 mL, 1.0 M). The reaction mixture wasstirred at 60° C. for 20 hrs. The reaction mixture was cooled to RT andacidified with 1.0 M HCl before extracting with EA. Organic layers werecombined and dried over Na₂SO₄. The solvent was removed under reducedpressure to afford 75A.

(S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-((R)-2-(trifluoromethyl)piperidin-1-yl)benzamido)propanoicacid (75): The title compound was prepared according to the methodpresented for the synthesis of compound 16A and 16 starting with 75A. MS(m/z) 645.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.90 (d, J=8.1 Hz, 1H),8.83 (dd, J=4.2, 1.6 Hz, 1H), 8.64 (dd, J=8.6, 1.7 Hz, 1H), 8.15 (dd,J=1.7, 0.4 Hz, 1H), 7.90 (dd, J=7.9, 1.7 Hz, 1H), 7.67-7.52 (m, 4H),6.72 (d, J=12.0 Hz, 2H), 4.93 (d, J=9.0 Hz, 1H), 4.70 (dt, J=9.7, 4.9Hz, 1H), 3.74 (s, 1H), 3.59 (d, J=12.9 Hz, 1H), 3.41 (s, 1H), 2.99 (t,J=12.2 Hz, 1H), 1.94 (d, J=14.4 Hz, 1H), 1.85-1.67 (m, 2H), 1.67-1.42(m, 3H).

Example 76

Synthesis of(R)-2,6-difluoro-4-(2-(trifluoromethyl)pyrrolidin-1-yl)benzoic acid(76A): The title compound was prepared according to the method presentedfor the synthesis of compound 75A starting with(R)-2-(trifluoromethyl)pyrrolidine.

(S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-((R)-2-(trifluoromethyl)pyrrolidin-1-yl)benzamido)propanoic acid (76): The title compoundwas prepared according to the method presented for the synthesis ofcompound 16A and 16 starting with 76A. MS (m/z) 629.5 [M+H]+. 1H NMR(400 MHz, DMSO-d6) δ 8.88 (d, J=8.2 Hz, 1H), 8.83 (dd, J=4.1, 1.6 Hz,1H), 8.65 (dd, J=8.7, 1.7 Hz, 1H), 8.15 (dd, J=1.7, 0.4 Hz, 1H),7.96-7.83 (m, 1H), 7.66-7.58 (m, 3H), 7.56 (dt, J=7.9, 0.6 Hz, 1H), 6.48(d, J=11.5 Hz, 2H), 4.82-4.63 (m, 2H), 3.72 (d, J=13.0 Hz, 1H), 3.56 (t,J=8.5 Hz, 1H), 3.41 (s, 1H), 3.15 (q, J=8.7 Hz, 1H), 2.16-1.91 (m, 4H).

Example 77

Synthesis of(R)-2,6-difluoro-4-(2-(trifluoromethyl)piperazin-1-yl)benzoic acid(77A): The title compound was prepared according to the method presentedfor the synthesis of compound 75A starting with(R)-2-(trifluoromethyl)piperazine.

(S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-((R)-2-(trifluoromethyl)piperazin-1-yl)benzamido)propanoic acid (77): The title compoundwas prepared according to the method presented for the synthesis ofcompound 16A and 16 starting with 77A. MS (m/z) 644.1 [M+H]+. 1H NMR(400 MHz, DMSO-d6) δ 8.94 (d, J=8.1 Hz, 1H), 8.83 (dd, J=4.1, 1.6 Hz,1H), 8.63 (dd, J=8.7, 1.7 Hz, 1H), 8.15 (dd, J=1.6, 0.4 Hz, 1H), 7.90(dd, J=7.9, 1.6 Hz, 1H), 7.67-7.57 (m, 3H), 7.58-7.53 (m, 1H), 6.79 (d,J=11.5 Hz, 2H), 4.71 (td, J=9.2, 8.2, 4.3 Hz, 1H), 4.26 (br, 1H), 4.05(d, J=13.2 Hz, 1H), 3.84 (d, J=10.9 Hz, 1H), 3.75 (s, 1H), 3.42 (s, 1H),3.29 (d, J=10.7 Hz, 1H), 3.12-2.96 (m, 3H).

Example 78

Synthesis of 2,6-difluoro-4-(2-(trifluoromethyl)azetidin-1-yl)benzoicacid (78A): The title compound was prepared according to the methodpresented for the synthesis of compound 75A starting with2-(trifluoromethyl)azetidine hydrochloride.

(2S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-(2-(trifluoromethyl)azetidin-1-yl)benzamido)propanoic acid (78): The title compound wasprepared according to the method presented for the synthesis of compound16A and 16 starting with 78A. MS (m/z) 617.1 [M+H]+. 1H NMR (400 MHz,DMSO-d6) δ 8.93 (dd, J=8.1, 3.2 Hz, 1H), 8.87-8.77 (m, 1H), 8.64 (dd,J=8.7, 1.7 Hz, 1H), 8.15 (d, J=1.7 Hz, 1H), 7.90 (dd, J=7.9, 1.6 Hz,1H), 7.67-7.50 (m, 4H), 6.24 (d, J=9.9 Hz, 2H), 4.91 (q, J=6.3 Hz, 1H),4.71 (d, J=9.6 Hz, 1H), 4.16-3.97 (m, 1H), 3.84-3.62 (m, 2H), 3.40 (s,1H), 2.68-2.53 (m, 1H), 2.37 (ddd, J=11.7, 5.6, 2.6 Hz, 1H).

Example 79

Synthesis of 2,6-difluoro-4-morpholinobenzoic acid (79A): The titlecompound was prepared according to the method presented for thesynthesis of compound 75A starting with morpholine.

(S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-morpholinobenzamido)propanoic acid (79): The title compound was prepared accordingto the method presented for the synthesis of compound 16A and 16starting with 79A. MS (m/z) 577.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ8.87 (d, J=8.0 Hz, 1H), 8.83 (dd, J=4.1, 1.6 Hz, 1H), 8.64 (dd, J=8.7,1.7 Hz, 1H), 8.15 (d, J=1.6 Hz, 1H), 7.96-7.84 (m, 1H), 7.67-7.58 (m,3H), 7.56 (d, J=7.9 Hz, 1H), 6.61 (d, J=11.8 Hz, 2H), 4.69 (q, J=5.9,4.3 Hz, 1H), 3.74 (s, 1H), 3.70-3.61 (m, 4H), 3.42 (s, 1H), 3.22-3.12(m, 4H).

Example 80

Synthesis of 4-(1,1-dioxidothiomorpholino)-2,6-difluorobenzoic acid(80A): The title compound was prepared according to the method presentedfor the synthesis of compound 75A starting with thiomorpholine1,1-dioxide.

(S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(4-(1,1-dioxidothiomorpholino)-2,6-difluorobenzamido)propanoicacid (80): The title compound was prepared according to the methodpresented for the synthesis of compound 16A and 16 starting with 80A. MS(m/z) 625.5 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.90 (d, J=8.1 Hz, 1H),8.84 (dd, J=4.1, 1.6 Hz, 1H), 8.64 (dd, J=8.6, 1.7 Hz, 1H), 8.15 (dd,J=1.7, 0.4 Hz, 1H), 7.90 (dd, J=7.9, 1.7 Hz, 1H), 7.67-7.58 (m, 3H),7.56 (dd, J=7.9, 0.4 Hz, 1H), 6.76 (d, J=11.7 Hz, 2H), 4.78-4.64 (m,1H), 3.85 (s, 4H), 3.75 (s, 1H), 3.42 (s, 1H), 3.06 (s, 4H).

Example 81

Synthesis of 2,6-difluoro-4-morpholinobenzoic acid (81A): The titlecompound was prepared according to the method presented for thesynthesis of compound 75A starting with 3-(trifluoromethyl)morpholinehydrochloride.

2,6-difluoro-4-(3-(trifluoromethyl) morpholino)benzoic acid (81): Thetitle compound was prepared according to the method presented for thesynthesis of compound 16A and 16 starting with 81A. MS (m/z) 645.1[M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.96 (dd, J=8.0, 2.7 Hz, 1H), 8.84(dd, J=4.1, 1.6 Hz, 1H), 8.65 (dd, J=8.7, 1.7 Hz, 1H), 8.16 (dd, J=1.6,0.4 Hz, 1H), 7.90 (dd, J=7.9, 1.6 Hz, 1H), 7.68-7.59 (m, 3H), 7.57 (dt,J=7.9, 0.6 Hz, 1H), 6.74 (d, J=11.7 Hz, 2H), 4.89 (dd, J=8.7, 3.6 Hz,1H), 4.71 (d, J=6.2 Hz, 1H), 4.14 (d, J=12.7 Hz, 1H), 3.93 (dd, J=11.5,3.8 Hz, 1H), 3.72 (d, J=13.0 Hz, 2H), 3.59-3.45 (m, 1H), 3.40 (d, J=12.7Hz, 2H), 3.21 (t, J=12.2 Hz, 1H).

Examples 82 and 83

Preparation of(S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamido)propanoicacid (82): 81 was separated into its 2 stereoisomers by supercriticalfluid chromatography using 25% MeOH/DEA co-solvent, at a flow rate of 50mL/min, using a Chiralpak AD-H 5 um 21×250 mm column. The title compoundwas identified as the first eluting peak. MS (m/z) 645.1 [M+H]⁺. 1H NMR(400 MHz, DMSO-d6) δ 8.78 (dd, J=4.2, 1.6 Hz, 1H), 8.74 (s, 1H), 8.14(dd, J=1.6, 0.4 Hz, 1H), 8.0-8.4 (br, 1H), 7.88 (dd, J=7.9, 1.7 Hz, 1H),7.61-7.49 (m, 4H), 6.74 (d, J=11.9 Hz, 2H), 4.88 (d, J=9.0 Hz, 1H), 4.43(s, 1H), 4.14 (d, J=12.7 Hz, 1H), 3.93 (dd, J=11.5, 3.7 Hz, 1H), 3.72(d, J=12.6 Hz, 2H), 3.60-3.48 (m, 1H), 3.41 (d, J=12.9 Hz, 1H), 3.21 (t,J=13.1 Hz, 2H).

Preparation of(S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-((S)-3-(trifluoromethyl)morpholino)benzamido)propanoicacid (83): 81 was separated into its 2 stereoisomers by supercriticalfluid chromatography using 25% EtOH/TFA cosolvent, at a flow rate of 50mL/min, using a Chiralpak AD-H 5 μm 21×250 mm column. The title compoundwas identified as the second eluting peak. MS (m/z) 645.1 [M+H]⁺. 1H NMR(400 MHz, DMSO-d6) δ 8.77 (dd, J=4.1, 1.5 Hz, 2H), 8.13 (dd, J=1.7, 0.4Hz, 1H), 8.08 (s, 1H), 7.88 (dd, J=7.9, 1.7 Hz, 1H), 7.65-7.42 (m, 4H),6.74 (d, J=11.9 Hz, 2H), 4.88 (dt, J=9.4, 4.7 Hz, 1H), 4.40 (d, J=6.6Hz, 1H), 4.14 (d, J=12.7 Hz, 1H), 3.93 (dd, J=11.5, 3.7 Hz, 1H), 3.71(d, J=13.0 Hz, 2H), 3.60-3.46 (m, 1H), 3.41 (d, J=13.0 Hz, 2H), 3.23 (d,J=11.8 Hz, 1H).

Example 84

Synthesis of (S)-2,6-difluoro-4-(2-methylmorpholino)benzoic acid (84A):The title compound was prepared according to the method presented forthe synthesis of compound 75A starting with (S)-2-methylmorpholine.

(S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-((S)-2-methylmorpholino)benzamido)propanoic acid (84): The title compound wasprepared according to the method presented for the synthesis of compound16A and 16 starting with 84A. MS (m/z) 591.8 [M+H]+. 1H NMR (400 MHz,DMSO-d6) δ 8.88 (d, J=8.1 Hz, 1H), 8.85 (dd, J=4.2, 1.5 Hz, 1H), 8.65(d, J=8.6 Hz, 1H), 8.17 (d, J=1.6 Hz, 1H), 7.91 (dd, J=7.9, 1.6 Hz, 1H),7.69-7.55 (m, 4H), 6.62 (d, J=11.9 Hz, 2H), 4.71 (t, J=11.2 Hz, 1H),3.87 (dd, J=11.2, 3.4 Hz, 1H), 3.71 (d, J=12.4 Hz, 2H), 3.66-3.50 (m,3H), 3.44 (s, 1H), 2.70 (td, J=11.8, 3.6 Hz, 1H), 2.38 (dd, J=12.3, 10.4Hz, 1H), 1.13 (d, J=6.2 Hz, 3H).

Example 85

Synthesis of (S)-2,6-difluoro-4-(2-methylmorpholino)benzoic acid (85A):The title compound was prepared according to the method presented forthe synthesis of compound 75A starting with(S)-2-(trifluoromethyl)morpholine.

(S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-((S)-2-(trifluoromethyl)morpholino)benzamido)propanoic acid (85): The title compound wasprepared according to the method presented for the synthesis of compound16A and 16 starting with 85A. MS (m/z) 645.1 [M+H]+. 1H NMR (400 MHz,DMSO-d6) δ 8.93 (d, J=8.1 Hz, 1H), 8.83 (dd, J=4.1, 1.6 Hz, 1H), 8.64(dd, J=8.7, 1.7 Hz, 1H), 8.16 (d, J=1.6 Hz, 1H), 7.90 (dd, J=7.9, 1.7Hz, 1H), 7.67-7.57 (m, 3H), 7.56 (d, J=7.9 Hz, 1H), 6.75 (d, J=11.6 Hz,2H), 4.77-4.66 (m, 1H), 4.29 (dq, J=6.7, 3.3 Hz, 1H), 4.03 (dd, J=10.9,3.3 Hz, 1H), 3.86 (d, J=12.2 Hz, 1H), 3.75 (m, 1H), 3.69 (t, J=10.4 Hz,2H), 3.41 (s, 1H), 2.92-2.72 (m, 2H).

Example 86

Synthesis of(R)-2,6-difluoro-4-((2,2,2-trifluoro-1-phenylethyl)amino)benzoic acid(86A): The title compound was prepared according to the method presentedfor the synthesis of compound 75A starting with(R)-2,2,2-trifluoro-1-phenylethan-1-amine.

(S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-(((R)-2,2,2-trifluoro-1-phenylethyl)amino)benzamido)propanoicacid (86): The title compound was prepared according to the methodpresented for the synthesis of compound 16A and 16 starting with 86A. MS(m/z) 665.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.85-8.77 (m, 2H), 8.61(dd, J=8.8, 1.7 Hz, 1H), 8.15 (dd, J=1.6, 0.4 Hz, 1H), 7.89 (dd, J=7.9,1.6 Hz, 1H), 7.66-7.48 (m, 7H), 7.46-7.32 (m, 3H), 6.53 (d, J=11.6 Hz,2H), 5.67 (q, J=8.7 Hz, 1H), 4.64 (d, J=11.6 Hz, 1H), 3.71 (s, 1H), 3.37(s, 1H).

Example 87

Synthesis of(R)-2,6-difluoro-4-(methyl(1,1,1-trifluoropropan-2-yl)amino)benzoic acid(87A): The title compound was prepared according to the method presentedfor the synthesis of compound 75A starting with(R)-1,1,1-trifluoro-N-methylpropan-2-amine.

(S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-(methyl((R)-1,1,1-trifluoropropan-2-yl)amino)benzamido)propanoicacid (87): The title compound was prepared according to the methodpresented for the synthesis of compound 16A and 16 starting with 87A. MS(m/z) 617.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.92-8.81 (m, 2H), 8.65(dd, J=8.7, 1.7 Hz, 1H), 8.16 (dd, J=1.7, 0.4 Hz, 1H), 7.90 (dd, J=7.9,1.6 Hz, 1H), 7.68-7.53 (m, 4H), 6.63 (d, J=12.0 Hz, 2H), 4.93 (p, J=7.4Hz, 1H), 4.70 (s, 1H), 3.74 (s, 1H), 3.41 (s, 1H), 2.83-2.77 (m, 3H),1.36 (d, J=6.8 Hz, 3H).

Example 88

Synthesis of2,6-difluoro-4-((1,1,1,3,3,3-hexafluoropropan-2-yl)amino)benzoic acid(88A): The title compound was prepared according to the method presentedfor the synthesis of compound 75A starting with1,1,1,3,3,3-hexafluoropropan-2-amine.

(S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-((1,1,1,3,3,3-hexafluoropropan-2-yl)amino)benzamido)propanoicacid (88): The title compound was prepared according to the methodpresented for the synthesis of compound 16A and 16 starting with 88A. MS(m/z) 657.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.93 (d, J=8.0 Hz, 1H),8.83 (dd, J=4.1, 1.6 Hz, 1H), 8.66-8.59 (m, 1H), 8.15 (d, J=1.7 Hz, 1H),7.90 (dd, J=7.8, 1.6 Hz, 1H), 7.67-7.53 (m, 5H), 6.69 (d, J=11.1 Hz,2H), 5.93 (s, 1H), 4.70 (s, 1H), 3.62 (s, 1H), 3.40 (s, 1H).

Example 89

Synthesis of4-((1-cyclopropyl-2,2,2-trifluoroethyl)amino)-2,6-difluorobenzoic acid(89A): The title compound was prepared according to the method presentedfor the synthesis of compound 75A starting with1-cyclopropyl-2,2,2-trifluoroethan-1-amine.

(2S)-3-(8-(2-chloro-4-cyanophenyl)quinolinn-5-yl)-2-(4-((1-cyclopropyl-2,2,2-trifluoroethyl)amino)-2,6-difluorobenzamido)propanoic acid (89): The titlecompound was prepared according to the method presented for thesynthesis of compound 16A and 16 starting with 89A. MS (m/z) 629.2[M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.86-8.75 (m, 2H), 8.63 (dd, J=8.7,1.6 Hz, 1H), 8.15 (dd, J=1.7, 0.4 Hz, 1H), 7.90 (dd, J=7.9, 1.6 Hz, 1H),7.67-7.53 (m, 4H), 6.93 (d, J=9.5 Hz, 1H), 6.40 (d, J=11.8 Hz, 2H), 4.67(s, 1H), 3.91 (q, J=8.1 Hz, 1H), 3.72 (s, 1H), 3.40 (s, 1H), 1.08-0.96(m, 1H), 0.60 (dq, J=8.5, 4.1, 3.3 Hz, 1H), 0.49 (dd, J=11.1, 5.8 Hz,2H), 0.34-0.23 (m, 1H).

Example 90

Preparation of(S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamido)propanoicacid (90): 89 was separated into its 2 stereoisomers by supercriticalfluid chromatography using 30% EtOH/TFA co-solvent, at a flow rate of 45mL/min, using an IE 5 μm 21×250 mm column. The title compound wasidentified as the first eluting peak. MS (m/z) 629.2 [M+H]⁺. 1H NMR (400MHz, DMSO-d6) δ 8.86-8.75 (m, 2H), 8.66-8.59 (m, 1H), 8.15 (dd, J=1.7,0.4 Hz, 1H), 7.90 (dd, J=7.9, 1.7 Hz, 1H), 7.67-7.49 (m, 4H), 6.92 (d,J=9.5 Hz, 1H), 6.40 (d, J=11.8 Hz, 2H), 4.67 (s, 1H), 3.91 (d, J=7.8 Hz,1H), 3.72 (s, 1H), 3.39 (s, 1H), 1.08-1.00 (m, 1H), 0.66-0.56 (m, 1H),0.53-0.42 (m, 2H), 0.33-0.26 (m, 1H).

Example 91

Synthesis of methyl(S)-3-(8-bromoquinolin-5-yl)-2-(tritylamino)propanoate (91A): To astirred solution of 1D (15 g, 43.4 mmol) in DCM was added TEA (15.12 mL,108.5 mmol) and trityl chloride (12.7 g, 45.57 mmol). The reactionmixture was stirred for 2 hours then filtered through celite, and washed3× with EA. The filtrate was concentrated and purified by silica gelchromatography eluting with EA/hexanes to give the title compound.

Synthesis of(S)-(5-(3-methoxy-3-oxo-2-(tritylamino)propyl)quinolin-8-yl)boronic acid(91B): The title compound was prepared according to the method presentedfor the synthesis of compound 4B starting with 91A.

Synthesis of methyl(S)-3-(8-(1,6-dimethyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)quinolin-5-yl)-2-(tritylamino)propanoate (91C): The titlecompound was prepared according to the method presented for thesynthesis of compound 11A starting with 91B and3-iodo-1,6-dimethyl-4-(trifluoromethyl)pyridin-2(1H)-one.

Synthesis of methyl(S)-2-amino-3-(8-(1,6-dimethyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)quinolin-5-yl)propanoate(91D): To a stirred solution of 91C (0.3 g, 0.46 mmol) in DCM was addedtriethylsilane (0.064 g, 0.49 mmol) and TFA (0.18 mL, 2.0 mmol). Thereaction mixture was allowed to stir at RT for 1 h then concentratedunder reduced pressure to give a material that was used without furtherpurification.

(S)-2-(2,6-difluoro-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)-3-(8-(1,6-dimethyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)quinolin-5-yl)propanoicacid (91): The title compound was prepared according to the methodpresented for the synthesis of compound 74 starting with 91D. MS (m/z)671.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.84-8.70 (m, 2H), 8.62 (s,1H), 7.55 (s, 2H), 7.42 (s, 1H), 6.75 (dd, J=9.4, 5.5 Hz, 1H), 6.54 (s,1H), 6.42 (dd, J=11.4, 4.2 Hz, 2H), 4.66 (s, 1H), 4.29 (s, 1H), 3.66 (d,J=13.6 Hz, 1H), 3.59-3.21 (m, 5H), 2.51 (s, 2H), 1.79-1.70 (m, 1H), 1.51(ddd, J=13.7, 10.4, 7.1 Hz, 1H), 0.91 (t, J=7.3 Hz, 3H).

Example 92

Synthesis of 2-chloro-4-methoxy-3-(trifluoromethyl)pyridine (92A): To astirred solution of 2,4-dichloro-3-(trifluoromethyl)pyridine (157.5 mg,0.729 mmol) in methanol at 0° C. was added sodium methoxide powder(118.19 mg, 2.188 mmol). The reaction mixture was allowed to warm to RTand was stirred for 16 hours. The solvent was removed under reducedpressure, and the resulting residue was purified by silica gelchromatography using EA in hexanes as eluent to afford the titlecompound.

Synthesis of methyl(S)-2-amino-3-(8-(4-methoxy-3-(trifluoromethyl)pyridin-2-yl)quinolin-5-yl)propanoate(92B): The title compound was prepared according to the method presentedfor the synthesis of compound 91C and 91D starting with 92A.

(S)-2-(2,6-difluoro-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)-3-(8-(4-methoxy-3-(trifluoromethyl)pyridin-2-yl)quinolin-5-yl)propanoicacid (92): The title compound was prepared according to the methodpresented for the synthesis of compound 74 starting with 92B. MS (m/z)657.8 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.80 (d, J=8.9 Hz, 2H), 8.73(d, J=5.9 Hz, 1H), 8.62 (t, J=7.9 Hz, 1H), 7.60 (t, J=6.8 Hz, 3H), 7.44(d, J=6.0 Hz, 1H), 6.76 (t, J=8.2 Hz, 1H), 6.45 (dd, J=11.7, 7.2 Hz,2H), 4.68 (d, J=19.6 Hz, 1H), 4.30 (s, 1H), 4.07 (s, 3H), 3.74 (d,J=15.1 Hz, 1H), 3.69-3.64 (m, 1H), 1.77 (s, 1H), 1.53 (s, 1H), 0.93 (t,J=7.4 Hz, 3H).

Example 93

Synthesis of (R)-2,6-difluoro-4-(3-(trifluoromethyl)morpholino)benzoicacid (93A): The title compound was prepared according to the methodpresented for the synthesis of compound 75A starting with(R)-3-(trifluoromethyl)morpholine.

(S)-2-(2,6-difluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(4-methoxy-3-(trifluoromethyl)pyridin-2-yl)quinolin-5-yl)propanoicacid (93): The title compound was prepared according to the methodpresented for the synthesis of compound 16A and 16 starting with 92B and93A. MS (m/z) 685.9 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 8.95 (dd,J=11.7, 8.0 Hz, 1H), 8.80 (d, J=3.7 Hz, 1H), 8.74 (d, J=6.0 Hz, 1H),8.63 (t, J=8.7 Hz, 1H), 7.61 (dd, J=13.0, 5.4 Hz, 3H), 7.46 (d, J=6.1Hz, 1H), 6.76 (t, J=11.2 Hz, 2H), 4.91 (d, J=9.3 Hz, 1H), 4.77-4.64 (m,1H), 4.19-4.13 (m, 1H), 4.08 (s, 3H), 3.95 (d, J=11.7 Hz, 1H), 3.80-3.66(m, 2H), 3.55 (t, J=11.8 Hz, 1H), 3.51-3.36 (m, 2H), 3.23 (t, J=12.5 Hz,1H).

Example 94

Synthesis of methyl(S)-3-(8-bromoquinolin-5-yl)-2-(2,6-difluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamido)propanoate(94A): The title compound was prepared according to the method presentedfor the synthesis of compound 16A in Example 16 starting with 93A.

Synthesis of(5-((S)-2-(2,6-difluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-methoxy-3-oxopropyl)quinolin-8-yl)boronic acid (94B): Thetitle compound was prepared according to the method presented for thesynthesis of compound 4B starting with 94A.

(S)-2-(2,6-difluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(5,6-dimethyl-3-(trifluoromethyl)pyridin-2-yl)quinolin-5-yl)propanoicacid (94): The title compound was prepared according to the methodpresented for the synthesis of compound 11A and 11 starting with 94B and2-chloro-5,6-dimethyl-3-(trifluoromethyl)pyridine. MS (m/z) 683.2[M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.96 (d, J=8.0 Hz, 1H), 8.77 (dd,J=4.0, 1.5 Hz, 1H), 8.67-8.59 (m, 1H), 8.03 (s, 1H), 7.68-7.47 (m, 3H),6.74 (d, J=11.7 Hz, 2H), 4.95-4.84 (m, 1H), 4.72-4.61 (m, 1H), 4.14 (d,J=12.8 Hz, 1H), 3.98-3.86 (m, 1H), 3.72 (d, J=13.1 Hz, 2H), 3.58-3.30(m, 3H), 3.21 (s, 1H), 2.50 (s, 3H), 2.41 (s, 3H).

Example 95

(S)-2-(2,6-difluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(1,4,6-trimethyl-2-oxo-1,2-dihydropyridin-3-yl)quinolin-5-yl)propanoicacid (95): The title compound was prepared according to the methodpresented for the synthesis of compound 11A and 11 starting with 94B and3-chloro-1,4,6-trimethylpyridin-2(1H)-one. MS (m/z) 645.2 [M+H]+. 1H NMR(400 MHz, DMSO-d6) δ 8.99-8.81 (m, 3H), 7.76 (s, 1H), 7.65 (dd, J=13.5,7.3 Hz, 1H), 7.53 (t, J=8.1 Hz, 1H), 6.72 (dd, J=11.5, 2.7 Hz, 2H), 6.20(s, 1H), 4.88 (d, J=9.4 Hz, 1H), 4.74-4.69 (m, 1H), 4.14 (d, J=12.7 Hz,1H), 3.93 (dd, J=11.5, 3.8 Hz, 1H), 3.79 (s, 1H), 3.70 (t, J=9.9 Hz,1H), 3.51 (d, J=10.7 Hz, 2H), 3.46-3.34 (m, 4H), 3.21 (t, J=12.3 Hz,1H), 2.40 (s, 3H), 1.73 (d, J=10.6 Hz, 3H).

Example 96

(S)-2-(2,6-difluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(1,6-dimethyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)quinolin-5-yl)propanoicacid (96): The title compound was prepared according to the methodpresented for the synthesis of compound 11A and 11 starting with 94B and3-iodo-1,6-dimethyl-4-(trifluoromethyl)pyridin-2(1H)-one. MS (m/z) 699.2[M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.96 (dd, J=7.9, 4.2 Hz, 1H),8.86-8.79 (m, 1H), 8.67 (s, 1H), 7.60 (dt, J=25.1, 8.5 Hz, 2H),7.48-7.39 (m, 1H), 6.74 (dd, J=11.6, 4.3 Hz, 2H), 6.54 (s, 1H), 4.90(dd, J=8.7, 3.6 Hz, 1H), 4.72-4.63 (m, 1H), 4.14 (d, J=12.7 Hz, 1H),3.93 (dd, J=11.5, 3.8 Hz, 1H), 3.75-3.62 (m, 2H), 3.60-3.32 (m, 6H),3.23 (d, J=12.4 Hz, 1H), 2.52 (s, 3H).

Example 97

(S)-2-(2,6-difluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(4,5-dimethylpyrimidin-2-yl)quinolin-5-yl)propanoicacid (97): The title compound was prepared according to the methodpresented for the synthesis of compound 11A and 11 starting with 94B and2-chloro-4,5-dimethylpyrimidine. MS (m/z) 617.0 [M+H]+. 1H NMR (400 MHz,DMSO-d6) δ 9.37 (s, 1H), 9.31 (s, 1H), 8.94 (d, J=8.3 Hz, 1H), 8.78 (s,2H), 8.11 (s, 1H), 7.93 (d, J=7.7 Hz, 1H), 6.77 (dd, J=37.8, 12.3 Hz,2H), 4.97-4.75 (m, 2H), 4.16 (dd, J=12.9, 8.0 Hz, 1H), 3.91 (ddd,J=25.2, 12.9, 4.2 Hz, 2H), 3.72 (d, J=13.1 Hz, 1H), 3.59-3.53 (m, 2H),3.41-3.36 (m, 1H), 3.22 (dd, J=14.4, 11.1 Hz, 1H), 2.66 (s, 3H), 2.39(s, 3H).

Example 98

(S)-2-(2,6-difluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(1-methyl-2-oxo-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)quinolin-5-yl)propanoicacid (98): The title compound was prepared according to the methodpresented for the synthesis of compound 11A and 11 starting with 94B and3-bromo-1-methyl-5-(trifluoromethyl)pyridin-2(1H)-one. MS (m/z) 685.2[M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 12.96 (s, 1H), 8.96 (d, J=8.0 Hz,1H), 8.89 (d, J=4.2 Hz, 1H), 8.71 (d, J=8.6 Hz, 1H), 8.50 (s, 1H),7.73-7.64 (m, 3H), 7.61 (d, J=7.3 Hz, 1H), 6.76 (d, J=11.8 Hz, 2H), 4.91(d, J=9.7 Hz, 1H), 4.68 (s, 1H), 4.16 (d, J=12.7 Hz, 1H), 3.95 (d,J=11.4 Hz, 1H), 3.73 (d, J=13.4 Hz, 2H), 3.57 (s, 4H), 3.44 (dd, J=14.0,9.3 Hz, 2H), 3.24 (t, J=12.5 Hz, 1H).

Example 99

(S)-2-(2,6-difluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(4-methoxy-6-methylpyrimidin-2-yl)quinolin-5-yl)propanoicacid (99): The title compound was prepared according to the methodpresented for the synthesis of compound 11A and 11 starting with 94B and2-chloro-4-methoxy-6-methylpyrimidine. MS (m/z) 632.2 [M+H]+. 1H NMR(400 MHz, DMSO-d6) δ 9.49 (d, J=4.9 Hz, 1H), 9.39 (d, J=8.7 Hz, 1H),9.04 (d, J=7.5 Hz, 1H), 8.95 (d, J=8.4 Hz, 1H), 8.18 (dd, J=8.7, 5.0 Hz,1H), 8.00 (d, J=7.8 Hz, 1H), 7.10 (s, 1H), 6.72 (d, J=12.2 Hz, 2H),4.94-4.78 (m, 2H), 4.15 (s, 4H), 4.00-3.84 (m, 2H), 3.74 (t, J=16.0 Hz,1H), 3.65-3.46 (m, 2H), 3.39 (d, J=12.8 Hz, 1H), 3.21 (t, J=12.5 Hz,1H), 2.70 (s, 3H).

Example 100

Synthesis of methyl(S)-2-amino-3-(8-(4-chloro-1,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)quinolin-5-yl)propanoate (100A): The title compound wasprepared according to the method presented for the synthesis of compound91C and 91D starting with 4-chloro-3-iodo-1,6-dimethylpyridin-2(1H)-one.

(S)-3-(8-(4-chloro-1,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)quinolin-5-yl)-2-(2,6-difluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamido)propanoicacid (100): The title compound was prepared according to the methodpresented for the synthesis of compound 93 starting with 100A. MS (m/z)665.7 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.98 (d, J=7.9 Hz, 1H), 8.87(d, J=4.3 Hz, 1H), 8.73 (s, 1H), 7.67 (d, J=9.1 Hz, 1H), 7.63 (dd,J=7.6, 4.2 Hz, 1H), 7.54 (d, J=7.3 Hz, 1H), 6.76 (dd, J=11.7, 3.9 Hz,2H), 6.49 (d, J=2.8 Hz, 1H), 4.91 (dd, J=8.9, 3.6 Hz, 1H), 4.70 (dd,J=12.5, 7.4 Hz, 1H), 4.16 (d, J=12.7 Hz, 1H), 3.97-3.93 (m, 2H), 3.73(dd, J=12.0, 8.5 Hz, 2H), 3.52 (d, J=22.8 Hz, 1H), 3.45 (d, J=1.9 Hz,3H), 3.41 (d, J=3.5 Hz, 1H), 3.24 (t, J=12.4 Hz, 1H), 2.46 (s, 3H).

Example 101

Synthesis of methyl(S)-2-amino-3-(8-(3-(dimethylamino)pyridin-2-yl)quinolin-5-yl)propanoate(101A): The title compound was prepared according to the methodpresented for the synthesis of compound 91C and 91D starting with2-bromo-N,N-dimethylpyridin-3-amine.

(S)-2-(2,6-difluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(3-(dimethylamino)pyridin-2-yl)quinolin-5-yl)propanoicacid (101): The title compound was prepared according to the methodpresented for the synthesis of compound 93 starting with 101A. MS (m/z)630.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.04-8.92 (m, 2H), 8.77 (dd,J=8.8, 1.6 Hz, 1H), 8.32 (d, J=5.3 Hz, 1H), 8.11 (d, J=8.8 Hz, 1H), 7.91(t, J=7.9 Hz, 2H), 7.81-7.71 (m, 2H), 6.74 (d, J=11.8 Hz, 2H), 4.90 (dd,J=8.8, 3.5 Hz, 1H), 4.81-4.72 (m, 1H), 4.16 (d, J=12.7 Hz, 1H), 3.96(dd, J=11.4, 3.7 Hz, 1H), 3.82 (dd, J=14.2, 4.4 Hz, 1H), 3.73 (d, J=12.8Hz, 1H), 3.62-3.36 (m, 3H), 3.23 (t, J=12.1 Hz, 1H), 2.50 (m, 6H).

Example 102

Synthesis of methyl(S)-2-amino-3-(8-(4-methoxy-1,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)quinolin-5-yl)propanoate(102A): The title compound was prepared according to the methodpresented for the synthesis of compound 91C and 91D starting with3-bromo-4-methoxy-1,6-dimethylpyridin-2(1H)-one.

(S)-2-(2,6-difluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(4-methoxy-1,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)quinolin-5-yl)propanoicacid (102): The title compound was prepared according to the methodpresented for the synthesis of compound 93 starting with 102A. MS (m/z)661.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 13.02 (s, 1H), 9.09 (s, 1H),9.04-8.93 (m, 2H), 7.91 (s, 1H), 7.71 (d, J=14.6 Hz, 2H), 6.76 (d,J=11.8 Hz, 2H), 6.46 (s, 1H), 4.92 (s, 1H), 4.72 (s, 1H), 4.16 (d,J=12.7 Hz, 1H), 4.00-3.91 (m, 1H), 3.70 (m, 5H), 3.61-3.37 (m, 6H), 3.23(t, J=12.3 Hz, 1H).

Example 103

Synthesis of 1,6-dimethyl-2-oxo-1,2-dihydropyridin-4-yl4-methylbenzenesulfonate (103A): To a stirred suspension of4-hydroxy-1,6-dimethylpyridin-2(1H)-one (1.5 g, 10.8 mmol) in TEA (1.8mL, 12.9 mmol) in DMF (27 mL) was added N-Ph triflimide (3.85 g, 10.8mmol). The reaction mixture was stirred for 15 min during which thesuspended solids went into solution. The solution was concentrated underreduced pressure and purified by silica gel chromatography using EA inhexanes to afford the title compound.

Synthesis of 4-(azetidin-1-yl)-1,6-dimethylpyridin-2(1H)-one (103B): Toa pressure tube was added 103A (450 mg, 1.66 mmol), azetidine (0.11 mL,1.66 mmol), XPhos Pd G3 (140 mg, 0.17 mmol), and Cs₂CO₃ (1.08 g, 3.3mmol) in toluene (5.5 mL). After sparging with N₂, the mixture washeated at 90° C. and allowed to stir vigorously for 90 min. The reactionmixture was cooled and filtered through a pad of Celite rinsing with EA.The solution was concentrated under reduced pressure and purified bysilica gel chromatography using MeOH in DCM to afford the titlecompound.

Synthesis of 4-(azetidin-1-yl)-3-iodo-1,6-dimethylpyridin-2(1H)-one(103C): To a stirred solution of 103B (90 mg, 0.5 mmol) in acetic acid(0.5 mL) was added N-iodosuccinimide (125 mg, 0.56 mmol). After 10 minconcentrated and added a 1:1 mixture of aq sat NaHCO₃ and aq satNa₂S₂O₃. The aqueous layer was extracted with EA. The organic layer waswashed with brine, dried over anhydrous Na₂SO₄, and concentrated underreduced pressure. The material was purified by silica gel chromatographyusing EA in hexanes to afford the title compound.

Synthesis of methyl(S)-2-amino-3-(8-(4-(azetidin-1-yl)-1,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)quinolin-5-yl)propanoate(103D): The title compound was prepared according to the methodpresented for the synthesis of compound 91C and 91D starting with 103C.

(S)-3-(8-(4-(azetidin-1-yl)-1,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)quinolin-5-yl)-2-(2,6-difluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamido)propanoicacid (103E): The title compound was prepared according to the methodpresented for the synthesis of compound 93 starting with 103D. MS (m/z)686.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.20 (s, 1H), 9.05 (d, J=4.9Hz, 1H), 8.91 (dd, J=8.3, 3.5 Hz, 1H), 7.98 (d, J=27.1 Hz, 1H),7.84-7.55 (m, 2H), 6.73 (dd, J=17.5, 11.8 Hz, 2H), 5.74 (d, J=2.8 Hz,1H), 4.90 (s, 1H), 4.82-4.70 (m, 1H), 4.16 (dd, J=12.6, 4.0 Hz, 1H),4.01-3.88 (m, 1H), 3.73 (d, J=13.2 Hz, 1H), 3.68-3.48 (m, 2H), 3.35 (d,J=5.2 Hz, 4H), 3.21 (s, 3H), 2.42-2.36 (m, 3H), 1.83 (dt, J=27.5, 7.6Hz, 1H).

Example 104

Synthesis of methyl(S)-2-amino-3-(1-methyl-2-oxo-1,2-dihydro-[3,8′-biquinolin]-5′-yl)propanoate(104A): The title compound was prepared according to the methodpresented for the synthesis of compound 91C and 91D starting with3-bromo-1-methylquinolin-2(1H)-one.

(S)-2-(2,6-difluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(1-methyl-2-oxo-1,2-dihydro-[3,8′-biquinolin]-5′-yl)propanoicacid (104): The title compound was prepared according to the methodpresented for the synthesis of compound 93 starting with 104A. MS (m/z)667.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.99 (1H, d, J=8.0 Hz), 8.90(1H, d, J=4.2 Hz), 8.79 (1H, m), 7.99 (1H, s), 7.82-7.58 (6H, m), 7.32(1H, t, J=7.4 Hz), 6.78 (2H, d, J=11.8 Hz), 4.95-4.88 (1H, m), 4.76-4.66(1H, m), 4.16 (1H, d, J=12.7 Hz), 3.96 (2H, dd, J=11.4, 3.9 Hz), 3.70(4H, m), 3.50 (3H, ddd, J=44.1, 17.5, 11.8 Hz), 3.24 (1H, t, J=12.6 Hz).

Example 105

Synthesis of 2-chloro-N,N-dimethyl-3-(trifluoromethyl)pyridin-4-amine(105A): The title compound was prepared according to the methodpresented for the synthesis of compound 92A in Example 92 starting withdimethyl amine.

Synthesis of methyl(S)-2-amino-3-(8-(4-(dimethylamino)-3-(trifluoromethyl)pyridin-2-yl)quinolin-5-yl)propanoate(105B): The title compound was prepared according to the methodpresented for the synthesis of compound 91C and 91D starting with 105A.

(S)-2-(2,6-difluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(4-(dimethylamino)-3-(trifluoromethyl)pyridin-2-yl)quinolin-5-yl)propanoicacid (105): The title compound was prepared according to the methodpresented for the synthesis of compound 93 starting with 105B. MS (m/z)698.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 13.08 (s, 1H), 9.00 (dd,J=30.1, 6.7 Hz, 2H), 8.74 (s, 1H), 8.38 (d, J=7.5 Hz, 1H), 7.96 (s, 1H),7.72 (d, J=21.3 Hz, 2H), 7.43 (d, J=7.4 Hz, 1H), 6.75 (d, J=11.7 Hz,2H), 4.91 (s, 1H), 4.74 (s, 1H), 4.16 (d, J=12.7 Hz, 1H), 3.96 (dd,J=11.4, 3.8 Hz, 1H), 3.85 (d, J=14.5 Hz, 1H), 3.74 (d, J=13.0 Hz, 2H),3.55 (t, J=12.1 Hz, 1H), 3.41 (d, J=12.5 Hz, 1H), 3.31 (s, 6H), 3.23 (s,1H).

Example 106

Synthesis of 1,4-dimethyl-5-(trifluoromethyl)pyridin-2(1H)-one (106A):To a stirred solution of 4-methyl-5-(trifluoromethyl)pyridin-2(1H)-one(100 mg, 0.056 mmol) in DMF was added NaH (25 mg, 0.62 mmol) and thereaction mixture was allowed to stir for 30 min at which time thebubbling ceased. The reaction mixture was cooled to 0° C. and methylp-toluene sulfonate (116 mg, 0.062 mmol) was added dropwise. After 4 hrsthe reaction mixture was allowed to warm to RT, concentrated underreduced pressure, and purified on silica gel chromatography eluting withHex/EA 0-100% to afford the title compound.

Synthesis of 3-iodo-1,4-dimethyl-5-(trifluoromethyl)pyridin-2(1H)-one(106B): To a stirred solution of 106A (0.72 g, 4 mmol) neat TFA wasadded TFAA (1.6 g, 8 mmol). The reaction mixture was heated to 100° C.for 5 min in a sealed vial, followed by the addition of NIS (1.08 g, 5mmol) and further heating at 60° C. for 3 hrs. The reaction mixture wascooled and the TFA removed under reduced pressure. The residue wasdissolved in EA and washed with sat. sodium bicarbonate then brine. Theorganic layer was filtered then concentrated to give the title compoundwithout further purification.

Synthesis of(S)-2-amino-3-(8-(1,4-dimethyl-2-oxo-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)quinolin-5-yl)propanoic acid (106C): The title compound wasprepared according to the method presented for the synthesis of compound91C and 91D starting with 106B.

(S)-2-(2,6-difluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(1,4-dimethyl-2-oxo-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)quinolin-5-yl)propanoicacid (106): The title compound was prepared according to the methodpresented for the synthesis of compound 93 starting with 106C. MS (m/z)699.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 12.94 (s, 1H), 8.94 (t, J=7.2Hz, 1H), 8.86 (t, J=3.0 Hz, 1H), 8.73 (d, J=8.4 Hz, 1H), 8.39 (s, 1H),7.74-7.58 (m, 2H), 7.53 (dd, J=11.4, 7.3 Hz, 1H), 6.74 (d, J=12.3 Hz,2H), 4.90 (d, J=9.0 Hz, 1H), 4.74 (dd, J=9.1, 5.0 Hz, 1H), 4.16 (d,J=12.7 Hz, 1H), 4.00-3.90 (m, 1H), 3.86-3.64 (m, 2H), 3.56 (d, J=13.1Hz, 1H), 3.51 (d, J=1.7 Hz, 3H), 3.46-3.31 (m, 2H), 3.23 (t, J=12.4 Hz,1H), 1.83 (d, J=10.2 Hz, 3H).

Example 107

Preparation of(S)-2-(2,6-difluoro-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)-3-(8-(1,6-dimethyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)quinolin-5-yl)propanoicacid (107): 91 was separated into its 2 atropisomeric enantiomers bysupercritical fluid chromatography using 30% MeOH co-solvent, at a flowrate of 60 mL/min, using an IC 5 μm 21×250 mm column. The title compoundwas identified as the first eluting peak. MS (m/z) 671.2 [M+H]⁺. 1H NMR(400 MHz, DMSO-d6) δ 8.85-8.72 (m, 2H), 8.63 (d, J=8.1 Hz, 1H),7.67-7.60 (m, 1H), 7.54 (d, J=7.2 Hz, 1H), 7.42 (d, J=7.3 Hz, 1H), 6.74(d, J=9.2 Hz, 1H), 6.54 (s, 1H), 6.42 (d, J=11.8 Hz, 2H), 4.66 (s, 1H),4.29 (s, 1H), 3.75-3.66 (m, 1H), 3.41 (m, 7H), 1.75 (s, 1H), 1.58-1.46(m, 1H), 0.91 (t, J=7.3 Hz, 3H).

Example 108

Synthesis of methyl(S)-3-(8-aminoquinolin-5-yl)-2-(tritylamino)propanoate (108A). To astirred solution of (91A) (1.148 g, 2.08 mmol) in dioxane (5 mL) wasadded cesium carbonate (2.04 g, 6 mmol), benzophenone imine, (755 mg,4.16 mmol), rac-Binap-Pd-G3 (103 mg, 0.1 mmol). The mixture was heatedat 90° C. overnight, cooled to RT diluted with THF and addedhydroxylamine hydrochloride (289 mg, 4.1 mmol) and sodium acetate (850mg, 6 mmol) and methanol (1 mL) and let stir for 4 h. The mixture wasdiluted with ethyl acetate and washed with water. The organic extractswere dried over magnesium sulfate and chromatographed on silica geleluting with hexanes and ethyl acetate to afford the title compound.

Synthesis of methyl(S)-3-(8-(5-(dimethylamino)-2-((ethoxycarbonyl)amino)benzamido)quinolin-5-yl)-2-(tritylamino)propanoate (108B). A stirredsolution of 2-amino-5-(dimethylamino)benzoic acid (299 mg, 1.6 mmol) andacetonitrile (3 mL) was cooled to 0° C. and added pyridine (672 uL, 8.3mmol), and ethyl chloroformate (0.635 mL, 6.645 mmol). The mixture wasremoved from an ice bath and let warm to RT over 30 minutes. Ethanol wasthen added and the mixture stirred a further 1 h. This entire mixturewas then added to 108A (675 mg, 1.38 mmol) dissolved in DMF (4 mL) andleft to stir for 4h. Solvents were removed on a rotary evaporator andthe product mixture was slurried with DCM and added to silica gel whichwas eluted with hexanes and ethyl acetate to provide the afford thetitle compound.

Synthesis of methyl(S)-3-(8-(6-(dimethylamino)-2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl)quinolin-5-yl)-2-(tritylamino)propanoate(108C). To a stirred solution of 108B (100 mg, 0.14 mmol) in DMF (2 mL)was added potassium carbonate (96 mg, 0.695 mmol) and methanol (1 mL).The mixture was stirred overnight and then the adsorbed directly ontosilica gel and chromatographed eluting with hexanes and ethyl acetate toafford the title compound.

Synthesis of methyl(S)-3-(8-(6-(dimethylamino)-1-methyl-2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl)quinolin-5-yl)-2-(tritylamino)propanoate (108D): Toa stirred solution of 108C (250 mg, 0.37 mol) in DMF (1 mL) was addedpotassium carbonate (51 mg, 0.37 mmol) and methyl tosylate (103 mg, 0.55mmol). The reaction mixture was stirred overnight and concentrated underreduced pressure to afford material that was chromatographed on silicagel column eluting with EA in hexane to afford the title compound.

Synthesis of methyl(S)-2-amino-3-(8-(6-(dimethylamino)-1-methyl-2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl)quinolin-5-yl)propanoate(108E). 108D was dissolved in DCM (1 mL) and added TFA (1 mL) and letstir for 4h. The mixture was concentrated and used without furtherpurification.

(S)-2-(2,6-difluoro-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)-3-(8-(6-(dimethylamino)-1-methyl-2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl)quinolin-5-yl)propanoicacid (108): The title compound was prepared according to the methodpresented for the synthesis of compound 74 starting with 108E. MS (m/z)699.8 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.00-8.79 (m, 2H), 8.64 (d,J=8.4 Hz, 1H), 7.78-7.55 (m, 3H), 7.44 (d, J=9.1 Hz, 1H), 7.37 (dd,J=9.5, 2.9 Hz, 1H), 7.25 (s, 1H), 6.78 (d, J=9.4 Hz, 1H), 6.45 (d,J=11.7 Hz, 3H), 5.74 (s, 1H), 4.66 (s, 1H), 3.51 (d, J=1.7 Hz, 3H),3.49-3.30 (m, 1H), 2.94 (s, 6H).

Example 109

Synthesis of N-(4-fluorophenyl)-N-methyl-3-oxobutanamide (109A): To asolution of 4-fluoro-N-methylaniline (0.500 g, 4.00 mmol) in toluene(4.0 mL) at 110° C. in an open vial (to evaporate off acetone-byproduct)was added 2,2,6-trimethyl-4H-1,3-dioxin-4-one (0.568 g, 4.00 mmol) andthe mixture was heated at 110° C. for 3 h. Upon completion, the solventwas evaporated off under reduced pressure. The material was purified byflash chromatography using EA in hexanes to afford the product (mixtureof keto and enol form).

Synthesis of 6-fluoro-1,4-dimethylquinolin-2(1H)-one (109B): A mixtureof 109A (0.250 g, 1.20 mmol) and concentrated H₂SO₄ (5.53 g, 56.4 mmol)was heated at 95° C. for 2 h. Upon completion, the reaction mixture waspoured over ice. The precipitate was filtered off to afford the productthat was used without further purification.

Synthesis of 6-fluoro-1,4-dimethylquinolin-2(1H)-one (109C): To amicrowave vial was added 109B (0.210 g, 1.10 mmol), NBS (0.489 g, 2.75mmol) and CH₃CN (11 mL), and the mixture was heated at 100° C. for 1 h.The precipitate was filtered off to afford the title compound and usedwithout further purification.

(S)-2-(2,6-difluoro-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)-3-(6-fluoro-1,4-dimethyl-2-oxo-1,2-dihydro-[3,8′-biquinolin]-5′-yl)propanoicacid (109): The title compound was prepared according to the methodpresented for the synthesis of compound 113 starting with 109C. MS (m/z)671.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.82 (dd, J=9.8, 6.2 Hz, 3H),7.80-7.49 (m, 6H), 6.76 (d, J=9.4 Hz, 1H), 6.49-6.38 (m, 2H), 4.72 (ddd,J=10.6, 8.3, 4.2 Hz, 1H), 4.29 (d, J=8.5 Hz, 2H), 3.81 (d, J=4.1 Hz,3H), 3.65 (d, J=2.6 Hz, 1H), 3.35 (dd, J=14.3, 10.5 Hz, 1H), 2.06 (d,J=9.3 Hz, 3H), 1.75 (ddd, J=13.8, 7.4, 3.3 Hz, 1H), 1.51 (ddd, J=13.7,10.4, 7.0 Hz, 1H), 0.91 (t, J=7.3 Hz, 3H).

Example 110

Synthesis of 2-oxo-1,2-dihydro-1,7-naphthyridine-3-carboxylic acid(110A): To a suspension of methyl2-oxo-1,2-dihydro-1,7-naphthyridine-3-carboxylate (0.109 g, 0.534 mmol)in THF/H₂O (1:1/0.76 mL) was added LiOH (64.0 mg, 2.67 mmol), and themixture was heated at 65° C. for 3 h. The precipitate was filtered offto afford the title compound and used without further purification.

Synthesis of 2-oxo-1,2-dihydro-1,7-naphthyridine-3-carboxylic acid(110B): To a microwave vial was added 110A (0.200 g, 1.05 mmol), NIS(0.828 g, 3.68 mmol), LiOAc (0.104 g, 1.58 mmol) and a mixture ofDMF/water (9:1, 12 mL). The reaction mixture was then stirred undermicrowave heating at 120° C. for 1 h. The solvent was removed underreduced pressure and the material was used without further purification.

Synthesis of 2-oxo-1,2-dihydro-1,7-naphthyridine-3-carboxylic acid(110C): To a solution of 110B (0.275 g, 1.01 mmol) in DMF (5 mL) at 0°C. was added NaH (32.0 mg, 1.00 mmol). The mixture was stirred for 5 minat 0° C., followed by the addition of iodomethane (0.187 g, 1.31 mmol).The cold bath was removed, and the mixture was stirred for 45 min at RT.Upon completion, the solvent was removed under reduced pressure and thematerial was purified by flash chromatography using MeOH in DCM (0-25%)to afford the title compound.

(S)-2-(2,6-difluoro-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)-3-(8-(1-methyl-2-oxo-1,2-dihydro-1,7-naphthyridin-3-yl)quinolin-5-yl)propanoicacid (110): The title compound was prepared according to the methodpresented for the synthesis of compound 113 starting with 110C. MS (m/z)640.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.01 (s, 1H), 8.87-8.79 (m,2H), 8.65 (s, 1H), 8.49 (d, J=5.1 Hz, 1H), 8.01 (s, 1H), 7.77-7.68 (m,2H), 7.65-7.57 (m, 2H), 6.78 (d, J=9.4 Hz, 1H), 6.50-6.42 (m, 2H),4.72-4.64 (m, 1H), 4.36-4.25 (m, 1H), 3.77 (s, 5H), 3.75-3.69 (m, 8H),3.43 (dd, J=13.8, 9.4 Hz, 3H), 1.83-1.73 (m, 1H), 1.60-1.47 (m, 1H),0.93 (t, J=7.4 Hz, 3H).

Example 111

Synthesis of 2-oxo-1,2-dihydro-1,7-naphthyridine-3-carboxylic acid(111A): To a suspension of methyl2-oxo-4-(trifluoromethyl)-1,2-dihydro-1,7-naphthyridine-3-carboxylate(0.109 g, 0.534 mmol) in THF/H₂O (1:1/0.76 mL) was added LiOH (64.0 mg,2.67 mmol), and the mixture was heated at 65° C. for 3 h. Theprecipitate was filtered off to afford the title compound and usedwithout further purification.

Synthesis of 2-oxo-1,2-dihydro-1,7-naphthyridine-3-carboxylic acid(111B): To a microwave vial was added 111A (0.200 g, 1.05 mmol), NIS(0.828 g, 3.68 mmol), LiOAc (0.104 g, 1.58 mmol) and a mixture ofDMF/water (9:1, 12 mL). The reaction mixture was then stirred undermicrowave heating at 120° C. for 1 h. The solvent was removed underreduced pressure and the material was used without further purification.

Synthesis of 2-oxo-1,2-dihydro-1,7-naphthyridine-3-carboxylic acid(111C): To a solution of 111B (0.275 g, 1.01 mmol) in DMF (5 mL) at 0°C. was added NaH (32.0 mg, 1.00 mmol). The mixture was stirred for 5 minat 0° C., followed by the addition of iodomethane (0.187 g, 1.31 mmol).The cold bath was removed, and the mixture was stirred for 45 min at RT.Upon completion, the solvent was removed under reduced pressure and thematerial was purified by flash chromatography using MeOH in DCM (0-25%)to afford the title compound.

(S)-2-(2,6-difluoro-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)-3-(8-(1-methyl-2-oxo-4-(trifluoromethyl)-1,2-dihydro-1,7-naphthyridin-3-yl)quinolin-5-yl)propanoicacid (111): The title compound was prepared according to the methodpresented for the synthesis of compound 113 starting with 111C. MS (m/z)708.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) b 9.15 (d, J=2.2 Hz, 1H),8.86-8.75 (m, 2H), 8.61 (t, J=8.8 Hz, 2H), 7.76 (d, J=5.2 Hz, 1H), 7.60(ddd, J=18.7, 8.8, 5.3 Hz, 3H), 7.24 (dd, J=36.0, 7.8 Hz, 1H), 6.76 (t,J=7.4 Hz, 1H), 6.57-6.36 (m, 2H), 4.70 (s, 1H), 4.32 (s, 1H), 3.79 (s,3H), 3.77-3.61 (m, 1H), 2.89 (d, J=2.2 Hz, 1H), 2.81-2.65 (m, 1H), 1.77(dd, J=14.3, 7.2 Hz, 1H), 1.61-1.44 (m, 1H), 1.24 (s, 1H), 0.93 (t,J=7.4 Hz, 3H).

Example 112

Synthesis of 2-oxo-1,2-dihydro-1,6-naphthyridine-3-carboxylic acid(112A): To a stirred solution of 4-aminonicotinaldehyde (0.15 g, 1.2mmol) in EtOH (2 mL) was added Meldrum's acid (0.17 g, 1.2 mmol),piperidine (10 μL, 0.13 mmol), and acetic acid (20 μL, 0.36 mmol). Thereaction mixture was stirred at RT for 20 min and then heated at 100° C.for 2 h. After cooling to RT, the product was filtered, washed withEtOH, and dried in vacuo to give the title compound.

Synthesis of 3-iodo-1,6-naphthyridin-2(1H)-one (112B): In a microwavevial (10 mL) that contained a solution of compound 112A (80 mg, 0.42mmol) in a mixture of DMF/water (9:1, 5 mL) were added NIS (331 mg, 1.47mmol) and LiOAc (42 mg, 0.63 mmol). The vial was sealed and then heatedunder microwave heating at 120° C. for 30 min. After cooling, water wasadded, and the mixture was extracted with DCM. The organic layer waswashed with brine, dried with Na₂SO₄, filtered, and concentrated underreduced pressure to give the title compound which was used withoutfurther purification.

Synthesis of 3-iodo-1-methyl-1,6-naphthyridin-2-one (112C): To a stirredsolution of compound 112B (114 mg, 0.42 mmol) in DMF (4 mL) at 0° C. wasadded sodium hydride (60%, 20 mg, 0.5 mmol) and the mixture was stirredfor 10 min at 0° C., followed by the addition of MeI (31 μL, 0.5 mmol).Ice bath was removed, and the reaction mixture was stirred at RT for 30minutes. EA and water was added to the reaction mixture. The organiclayer was washed with brine, dried over anhydrous Na₂SO₄, andconcentrated under reduced pressure. The material was purified by silicagel chromatography using MeOH in DCM as eluent to afford the titlecompound.

(S)-2-(2,6-difluoro-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)-3-(8-(1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)quinolin-5-yl)propanoicacid (112): The title compound was prepared according to the methodpresented for the synthesis of compound 113 starting with 112C. MS (m/z)640.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.16 (s, 1H), 8.87-8.81 (m,2H), 8.79 (d, J=6.6 Hz, 1H), 8.67 (d, J=8.6 Hz, 1H), 8.19 (s, 1H), 7.87(d, J=6.6 Hz, 1H), 7.72 (d, J=7.3 Hz, 1H), 7.67 (dd, J=8.6, 4.2 Hz, 1H),7.63 (d, J=7.4 Hz, 1H), 6.78 (d, J=9.4 Hz, 1H), 6.46 (d, J=11.6 Hz, 2H),4.76-4.61 (m, 1H), 4.31 (d, J=8.8 Hz, 1H), 3.76 (d, J=4.6 Hz, 1H), 3.73(s, 3H), 3.43 (dd, J=14.5, 9.9 Hz, 1H), 1.78 (ddd, J=13.7, 7.2, 3.2 Hz,1H), 1.61-1.50 (m, 1H), 0.93 (t, J=7.3 Hz, 3H).

Example 113

Synthesis of methyl(S)-3-(8-bromoquinolin-5-yl)-2-(2,6-difluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamido)propanoate (113A): The title compound wasprepared according to the method presented for the synthesis of compound16A in Example 16 starting with 74C.

Synthesis of(5-((S)-2-(2,6-difluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-methoxy-3-oxopropyl)quinolin-8-yl)boronicacid (113B): The title compound was prepared according to the methodpresented for the synthesis of compound 4B starting with 113A.

(S)-2-(2,6-difluoro-4-(((R)-1,1,1,1-trifluorobutan-2-yl)amino)benzamido)-3-(8-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)quinolin-5-yl)propanoicacid (113): The title compound was prepared according to the methodpresented for the synthesis of compound 11A and 11 starting with 113Band 5-bromo-1,3-dimethylpyrimidine-2,4(1H,3H)-dione. MS (m/z) 620.2[M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.98-8.83 (m, 1H), 8.78 (dd, J=15.0,8.3 Hz, 2H), 7.92 (s, 1H), 7.79-7.64 (m, 2H), 7.60 (d, J=7.4 Hz, 1H),6.84-6.69 (m, 1H), 6.43 (d, J=11.6 Hz, 2H), 4.63 (td, J=9.3, 4.5 Hz,1H), 4.30 (d, J=10.0 Hz, 1H), 3.70 (dd, J=14.4, 4.5 Hz, 1H), 3.39 (s,4H), 3.24 (s, 3H), 1.75 (ddt, J=15.0, 7.7, 3.9 Hz, 1H), 1.51 (ddt,J=17.8, 14.5, 7.3 Hz, 1H), 0.91 (t, J=7.3 Hz, 3H).

Example 114

(S)-2-(2,6-difluoro-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)-3-(8-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)quinolin-5-yl)propanoicacid (114): The title compound was prepared according to the methodpresented for the synthesis of compound 11A and 11 starting with 113Band 5-bromo-1,3,6-trimethylpyrimidine-2,4(1H,3H)-dione. MS (m/z) 634.2[M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.91 (d, J=4.3 Hz, 1H), 8.78 (dd,J=8.0, 2.3 Hz, 1H), 7.76-7.44 (m, 3H), 6.78-6.67 (m, 1H), 6.41 (dd,J=11.3, 3.5 Hz, 2H), 4.73-4.57 (m, 1H), 4.29 (s, 1H), 3.72 (ddd, J=56.2,14.3, 4.5 Hz, 1H), 3.45 (d, J=1.6 Hz, 4H), 3.21 (d, J=2.4 Hz, 3H), 1.92(d, J=10.1 Hz, 3H), 1.75 (ddd, J=13.6, 7.3, 3.2 Hz, 1H), 1.50 (ddd,J=13.7, 10.3, 7.0 Hz, 1H), 0.90 (t, J=7.3 Hz, 3H).

Example 115

(S)-2-(2,6-difluoro-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)-3-(8-(1,4,5,6-tetramethyl-2-oxo-1,2-dihydropyridin-3-yl)quinolin-5-yl)propanoicacid (115): The title compound was prepared according to the methodpresented for the synthesis of compound 11A and 11 starting with 113Band 3-bromo-1,4,5,6-tetramethylpyridin-2(1H)-one. MS (m/z) 631.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.91-8.86 (m, 1H), 8.79 (dd, J=7.8, 3.0 Hz,1H), 7.80-7.71 (m, 1H), 7.66 (dd, J=11.8, 7.3 Hz, 1H), 7.50 (t, J=7.8Hz, 1H), 6.76 (dd, J=9.2, 4.4 Hz, 1H), 6.47-6.39 (m, 2H), 4.77-4.66 (m,1H), 4.36-4.25 (m, 1H), 3.71-3.64 (m, 2H), 3.53 (s, 1H), 3.49 (s, 3H),3.37 (dd, J=13.8, 10.2 Hz, 1H), 2.43 (s, 3H), 2.32 (s, 1H), 2.09 (d,J=6.8 Hz, 3H), 1.75 (d, J=10.8 Hz, 3H), 1.58-1.47 (m, 1H), 0.92 (t,J=7.3 Hz, 3H).

Example 116

(S)-3-(8-(5-chloro-1,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)quinolin-5-yl)-2-(2,6-difluoro-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)propanoicacid (116): The title compound was prepared according to the methodpresented for the synthesis of compound 11A and 11 starting with 113Band 3-bromo-5-chloro-1,6-dimethylpyridin-2(1H)-one. MS (m/z) 637.3[M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.96 (dd, J=4.5, 1.5 Hz, 1H), 8.87(d, J=8.5 Hz, 1H), 8.81 (d, J=8.0 Hz, 1H), 7.82-7.72 (m, 2H), 7.65 (d,J=7.5 Hz, 1H), 7.58 (s, 1H), 6.78 (d, J=9.4 Hz, 1H), 6.45 (d, J=11.7 Hz,2H), 4.72-4.62 (m, 1H), 4.37-4.23 (m, 1H), 3.74 (dd, J=14.5, 4.6 Hz,1H), 3.56 (s, 3H), 3.44 (dd, J=14.5, 9.8 Hz, 1H), 2.58 (s, 3H),1.84-1.70 (m, 1H), 1.60-1.45 (m, 1H), 0.93 (t, J=7.3 Hz, 3H).

Example 117

(S)-2-(2,6-difluoro-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)-3-(8-(4,5,6-trimethyl-3-oxo-3,4-dihydropyrazin-2-yl)quinolin-5-yl)propanoicacid (117): The title compound was prepared according to the methodpresented for the synthesis of compound 11A and 11 starting with 113Band 3-chloro-1,5,6-trimethylpyrazin-2(1H)-one. MS (m/z) 618.2 [M+H]+. 1HNMR (400 MHz, DMSO-d6) δ 8.91 (d, J=4.4 Hz, 1H), 8.80 (d, J=7.9 Hz, 2H),7.84-7.69 (m, 2H), 7.64 (d, J=7.4 Hz, 1H), 6.78 (d, J=9.4 Hz, 1H), 6.45(d, J=11.6 Hz, 2H), 4.68 (dt, J=8.6, 4.1 Hz, 1H), 4.36-4.29 (m, 1H),3.73 (dd, J=14.4, 4.6 Hz, 1H), 3.53 (s, 3H), 3.45 (dd, J=14.4, 9.7 Hz,1H), 2.42 (s, 3H), 2.34 (s, 3H), 1.77 (ddd, J=13.8, 7.2, 3.3 Hz, 1H),1.57-1.47 (m, 1H), 0.93 (t, J=7.3 Hz, 3H).

Example 118

(S)-2-(2,6-difluoro-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)-3-(8-(1,2-dimethyl-6-oxo-1,6-dihydropyrimidin-5-yl)quinolin-5-yl)propanoicacid (118): The title compound was prepared according to the methodpresented for the synthesis of compound 11A and 11 starting with 113Band 5-bromo-2,3-dimethylpyrimidin-4(3H)-one. MS (m/z) 604.2 [M+H]+. 1HNMR (400 MHz, DMSO-d6) δ 8.89 (dd, J=4.3, 1.5 Hz, 1H), 8.80 (d, J=7.9Hz, 1H), 8.70 (d, J=8.6 Hz, 1H), 7.95 (s, 1H), 7.68 (dd, J=7.9, 3.9 Hz,2H), 7.59 (d, J=7.4 Hz, 1H), 6.77 (d, J=9.4 Hz, 1H), 6.44 (d, J=11.5 Hz,2H), 4.70-4.55 (m, 1H), 4.30 (s, 1H), 3.70 (dd, J=14.4, 4.6 Hz, 1H),3.53 (s, 3H), 3.41 (dd, J=14.5, 9.8 Hz, 1H), 2.62 (s, 3H), 1.77 (ddd,J=13.7, 7.3, 3.2 Hz, 1H), 1.52 (ddd, J=13.7, 10.4, 7.2 Hz, 1H), 0.92 (t,J=7.3 Hz, 3H).

Example 119

(S)-2-(2,6-difluoro-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)-3-(8-(1,4-dimethyl-6-oxo-1,6-dihydropyridazin-3-yl)quinolin-5-yl)propanoicacid (119): The title compound was prepared according to the methodpresented for the synthesis of compound 11A and 11 starting with 113Band 6-chloro-2,5-dimethylpyridazin-3(2H)-one. MS (m/z) 604.2 [M+H]+. 1HNMR (400 MHz, DMSO-d6) δ 8.87 (dd, J=4.2, 1.5 Hz, 1H), 8.76 (d, J=8.1Hz, 1H), 8.64 (dd, J=8.7, 1.6 Hz, 1H), 7.70-7.56 (m, 3H), 6.86 (d, J=1.4Hz, 1H), 6.75 (d, J=9.4 Hz, 1H), 6.42 (d, J=11.6 Hz, 2H), 4.67 (t,J=11.3 Hz, 1H), 4.29 (d, J=9.4 Hz, 1H), 3.72 (dd, J=14.3, 4.5 Hz, 1H),3.64 (s, 3H), 3.39 (dd, J=14.3, 10.1 Hz, 1H), 1.74 (d, J=1.2 Hz, 4H),1.50 (ddd, J=13.7, 10.4, 7.1 Hz, 1H), 0.90 (t, J=7.3 Hz, 3H).

Example 120

(S)-2-(2,6-difluoro-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)-3-(8-(3-methoxy-6-methylpyridin-2-yl)quinolin-5-yl)propanoicacid (120): The title compound was prepared according to the methodpresented for the synthesis of compound 11A and 11 starting with 113Band 2-bromo-3-methoxy-6-methylpyridine. MS (m/z) 603.2 [M+H]+. 1H NMR(400 MHz, DMSO-d6) δ 8.88 (dd, J=11.7, 5.9 Hz, 2H), 8.74 (d, J=8.6 Hz,1H), 8.16 (s, 1H), 7.85 (d, J=24.9 Hz, 2H), 7.71 (d, J=7.1 Hz, 2H), 6.79(d, J=9.4 Hz, 1H), 6.46 (d, J=12.0 Hz, 2H), 4.70 (s, 1H), 4.31 (d,J=10.1 Hz, 1H), 3.79 (s, 4H), 3.50-3.41 (m, 1H), 2.62 (s, 3H), 1.77 (s,1H), 1.54 (dd, J=15.7, 7.7 Hz, 1H), 0.93 (t, J=7.0 Hz, 3H).

Example 121

Synthesis of 4-(4-bromo-3,5-dimethoxybenzyl)morpholine (121A): To astirred solution of (4-bromo-3,5-dimethoxyphenyl)methanol (300 mg, 1.214mmol) in DCM (3 mL) was added N,N-diisopropylethyl amine (0.306 mL,2.428 mmol). Methanesulfonyl chloride (0.094 mL, 1.214 mmol) was addeddropwise and the reaction mixture was allowed to stir at RT for 5 min.Morpholine (0.134 mL, 3.642 mmol) was added dropwise and the reactionmixture was allowed to stir at RT for 14 hrs. The reaction mixture wasconcentrated under reduced pressure, dissolved in toluene (2 mL) andagain concentrated under reduced pressure to afford the title compoundwithout further purification.

(S)-2-(2,6-difluoro-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)-3-(8-(2,6-dimethoxy-4-(morpholinomethyl)phenyl)quinolin-5-yl)propanoicacid (121): The title compound was prepared according to the methodpresented for the synthesis of compound 5B and 5 starting with 113B and121A. MS (m/z) 717.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 12.93 (s, 1H),10.01 (s, 1H), 8.84 (d, J=7.9 Hz, 1H), 8.75 (dd, J=4.2, 1.6 Hz, 1H),8.60 (d, J=8.5 Hz, 1H), 7.57 (dd, J=16.9, 8.0 Hz, 2H), 7.40 (d, J=7.3Hz, 1H), 6.91 (q, J=1.3 Hz, 2H), 6.78 (d, J=9.4 Hz, 1H), 6.44 (d, J=11.5Hz, 2H), 4.66 (td, J=8.8, 8.1, 4.3 Hz, 1H), 4.39 (s, 2H), 4.30 (d, J=9.5Hz, 1H), 4.02 (d, J=12.6 Hz, 2H), 3.70 (t, J=12.1 Hz, 5H), 3.58 (d,J=5.6 Hz, 6H), 3.38 (dd, J=14.2, 10.2 Hz, 3H), 3.19 (d, J=10.8 Hz, 3H),1.76 (ddt, J=10.7, 7.3, 3.1 Hz, 1H), 1.51 (ddt, J=17.5, 14.2, 7.3 Hz,1H), 0.91 (t, J=7.3 Hz, 3H).

Example 122

Synthesis of methyl(S)-2-amino-3-(4-methoxy-1-methyl-2-oxo-1,2-dihydro-[3,8′-biquinolin]-5′-yl)propanoate(122A): The title compound was prepared according to the methodpresented for the synthesis of compound 91C and 91D starting with3-bromo-4-methoxy-1-methylquinolin-2(1H)-one.

(S)-2-(2,6-difluoro-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)-3-(4-methoxy-1-methyl-2-oxo-1,2-dihydro-[3,8′-biquinolin]-5′-yl)propanoicacid (122): The title compound was prepared according to the methodpresented for the synthesis of compound 74 starting with 122A. MS (m/z)669.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.95 (d, J=5.1 Hz, 2H), 8.81(dd, J=8.2, 2.6 Hz, 1H), 7.97 (dt, J=8.0, 1.9 Hz, 1H), 7.89-7.66 (m,4H), 7.68-7.59 (m, 1H), 7.42-7.32 (m, 1H), 6.77 (d, J=9.4 Hz, 1H), 6.44(dd, J=11.5, 8.0 Hz, 2H), 4.80-4.69 (m, 1H), 4.37-4.22 (m, 1H),3.76-3.52 (m, 4H), 3.30 (d, J=2.1 Hz, 3H), 1.84-1.70 (m, 1H), 1.61-1.44(m, 1H), 0.92 (td, J=7.4, 2.4 Hz, 3H).

Example 123

Synthesis of 3-iodo-1-methyl-4-(trifluoromethyl)quinolin-2(1H)-one(123A): To a stirred solution of1-methyl-4-(trifluoromethyl)quinolin-2(1H)-one (243 mg, 1.07 mmol) inTHF was added LiMg-TMP (1.74 mL, 1M) dropwise at −78° C. The reactionmixture was allowed to stir for 30 min, then a solution of iodine (488mg, 2 mmol) in THF was then added at −78° C. The reaction mixture wasallowed to warm to RT then was concentrated under reduced pressure, andpurified by silica gel chromatography using EA/hexanes as the eluent toafford the title compound.

(S)-2-(2,6-difluoro-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)-3-(1-methyl-2-oxo-4-(trifluoromethyl)-1,2-dihydro-[3,8′-biquinolin]-5′-yl)propanoicacid (123): The title compound was prepared according to the methodpresented for the synthesis of compound 11A and 11 starting with 113Band 123A. MS (m/z) 707.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.85-8.77(m, 2H), 8.65 (d, J=8.6 Hz, 1H), 7.91 (d, J=8.1 Hz, 1H), 7.85-7.72 (m,2H), 7.67-7.57 (m, 2H), 7.54 (t, J=7.3 Hz, 1H), 7.46 (t, J=7.7 Hz, 1H),6.76 (dd, J=9.4, 5.6 Hz, 1H), 6.45 (dd, J=11.4, 3.7 Hz, 2H), 4.70 (tt,J=8.8, 4.7 Hz, 1H), 4.39-4.24 (m, 1H), 3.80-3.63 (m, 4H), 3.44 (ddd,J=35.4, 14.5, 9.8 Hz, 1H), 1.85-1.69 (m, 1H), 1.60-1.43 (m, 1H), 0.93(t, J=7.3 Hz, 3H).

Example 124

Synthesis of 3-iodo-1-methyl-4-(trifluoromethyl)quinolin-2(1H)-one(124A): The title compound was prepared according to the methodpresented for the synthesis of compound 123A starting with6-fluoro-1-methyl-4-(trifluoromethyl)quinolin-2(1H)-one.

(S)-2-(2,6-difluoro-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)-3-(1-methyl-2-oxo-4-(trifluoromethyl)-1,2-dihydro-[3,8′-biquinolin]-5′-yl)propanoicacid (124): The title compound was prepared according to the methodpresented for the synthesis of compound 11A and 11 starting with 113Band 124A. MS (m/z) 724.9 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.95-8.70(m, 2H), 8.62 (d, J=8.6 Hz, 1H), 6.75 (dd, J=9.4, 5.6 Hz, 1H), 6.43 (dd,J=11.3, 3.7 Hz, 2H), 4.76-4.62 (m, 1H), 4.28 (s, 2H), 3.69 (d, J=2.0 Hz,3H), 3.43 (d, J=47.0 Hz, 1H), 1.89-1.69 (m, 1H), 1.51 (dt, J=17.5, 7.4Hz, 1H), 0.91 (t, J=7.3 Hz, 3H).

Example 125

Synthesis of 3-iodo-1-methyl-4-(trifluoromethyl)quinolin-2(1H)-one(125A): The title compound was prepared according to the methodpresented for the synthesis of compound 123A starting with6-(dimethylamino)-1-methyl-4-(trifluoromethyl)quinolin-2(1H)-one.

(S)-2-(2,6-difluoro-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)-3-(6-(dimethylamino)-1-methyl-2-oxo-4-(trifluoromethyl)-1,2-dihydro-[3,8′-biquinolin]-5′-yl)propanoicacid (125): The title compound was prepared according to the methodpresented for the synthesis of compound 11A and 11 starting with 113Band 125A. MS (m/z) 724.9 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.95-8.70(m, 2H), 8.62 (d, J=8.6 Hz, 1H), 6.75 (dd, J=9.4, 5.6 Hz, 1H), 6.43 (dd,J=11.3, 3.7 Hz, 2H), 4.76-4.62 (m, 1H), 4.28 (s, 2H), 3.69 (d, J=2.0 Hz,3H), 3.43 (d, J=47.0 Hz, 1H), 1.89-1.69 (m, 1H), 1.51 (dt, J=17.5, 7.4Hz, 1H), 0.91 (t, J=7.3 Hz, 3H).

Example 126

Synthesis of3-iodo-1-methyl-4-(trifluoromethyl)-1,5,6,7-tetrahydro-2H-cyclopenta[b]pyridin-2-one (126A): The title compound was prepared according tothe method presented for the synthesis of compound 123A starting with1-methyl-4-(trifluoromethyl)-1,5,6,7-tetrahydro-2H-cyclopenta[b]pyridin-2-one.

(S)-2-(2,6-difluoro-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)-3-(8-(1-methyl-2-oxo-4-(trifluoromethyl)-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl)quinolin-5-yl)propanoicacid (126): The title compound was prepared according to the methodpresented for the synthesis of compound 11A and 11 starting with 113Band 126A. MS (m/z) 697.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.89-8.75(m, 2H), 8.68 (d, J=8.1 Hz, 1H), 7.65 (dt, J=8.9, 4.9 Hz, 1H), 7.58 (dd,J=7.4, 5.8 Hz, 1H), 7.43 (dd, J=7.3, 5.4 Hz, 1H), 6.76 (dd, J=9.4, 6.4Hz, 1H), 6.56 (q, J=1.1 Hz, 1H), 6.44 (dd, J=11.4, 4.9 Hz, 2H),4.77-4.53 (m, 1H), 4.30 (s, 1H), 3.86-3.56 (m, 1H), 3.10 (q, J=7.2, 6.8Hz, 2H), 2.98 (dt, J=17.6, 7.4 Hz, 3H), 2.85-2.72 (m, 2H), 2.24-1.98 (m,3H), 1.89-1.67 (m, 1H), 1.53 (ddd, J=13.7, 10.3, 7.0 Hz, 1H), 0.93 (t,J=7.3 Hz, 3H).

Example 127

(S)-2-(2,6-difluoro-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)-3-(6-fluoro-1,2-dimethyl-4-oxo-1,4-dihydro-[3,8′-biquinolin]-5′-yl)propanoicacid (127): The title compound was prepared according to the methodpresented for the synthesis of compound 11A and 11 starting with 113Band 3-bromo-6-fluoro-1,2-dimethylquinolin-4(1H)-one. MS (m/z) 671.2[M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.87 (d, J=3.9 Hz, 2H), 8.84-8.78(m, 1H), 8.01 (dd, J=9.6, 4.4 Hz, 1H), 7.84-7.79 (m, 1H), 7.78-7.65 (m,3H), 7.60 (dd, J=12.7, 8.4 Hz, 1H), 6.76 (dd, J=10.0, 2.5 Hz, 1H), 6.44(d, J=13.0 Hz, 2H), 4.78-4.68 (m, 1H), 4.35-4.25 (m, 2H), 3.90-3.88 (m,3H), 3.84 (dd, J=14.8, 3.8 Hz, 1H), 3.71-3.66 (m, 1H), 3.58-3.51 (m,1H), 3.38 (dd, J=14.6, 10.5 Hz, 1H), 2.16 (d, J=8.7 Hz, 3H), 1.83-1.71(m, 1H), 1.59-1.47 (m, 1H), 0.93 (t, J=7.4 Hz, 3H).

Example 128

Synthesis of(R)-2,6-difluoro-4-((1,1,1-trifluoropropan-2-yl)amino)benzoic acid(128A): The title compound was prepared according to the methodpresented for the synthesis of compound 75A Example 75 starting with(R)-1,1,1-trifluoropropan-2-amine.

(S)-2-(2,6-difluoro-4-(((R)-1,1,1-trifluoropropan-2-yl)amino)benzamido)-3-(8-(1,6-dimethyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)quinolin-5-yl)propanoicacid (128): The title compound was prepared according to the methodpresented for the synthesis of compound 16A and 16 starting with 91D and128A. MS (m/z) 657.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.80 (t, J=6.0Hz, 2H), 8.60 (d, J=8.7 Hz, 1H), 7.63-7.51 (m, 2H), 7.46-7.33 (m, 1H),6.88-6.76 (m, 1H), 6.53 (s, 1H), 6.40 (dd, J=11.2, 4.3 Hz, 2H), 4.65(dt, J=13.4, 4.7 Hz, 1H), 4.50 (dd, J=15.4, 7.7 Hz, 1H), 3.73-3.56 (m,2H), 3.47 (d, J=2.2 Hz, 4H), 3.16-3.03 (m, 1H), 2.51 (s, 2H), 1.27-1.23(m, 4H).

Example 129

(S)-2-(2,6-difluoro-4-((R)-2-(trifluoromethyl)piperidin-1-yl)benzamido)-3-(8-(1,6-dimethyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)quinolin-5-yl)propanoicacid (129): The title compound was prepared according to the methodpresented for the synthesis of compound 75 starting with 91D. MS (m/z)697.8 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.92 (dd, J=7.8, 4.2 Hz, 1H),8.86 (d, J=4.0 Hz, 1H), 8.73 (d, J=7.7 Hz, 1H), 7.74-7.64 (m, 1H), 7.61(t, J=7.7 Hz, 1H), 7.48 (dd, J=7.1, 3.7 Hz, 1H), 6.73 (dd, J=11.9, 4.0Hz, 2H), 6.57 (s, 1H), 5.00-4.87 (m, 1H), 4.77-4.71 (m, 1H), 3.73 (td,J=19.1, 14.5, 4.2 Hz, 1H), 3.66-3.56 (m, 1H), 3.53-3.37 (m, 4H), 3.02(t, J=12.4 Hz, 1H), 2.54 (s, 3H), 1.97 (d, J=14.5 Hz, 1H), 1.87-1.67 (m,2H), 1.67-1.43 (m, 3H).

Example 130

Synthesis of (S)-4-(3-(2,2-difluoroethyl)morpholino)-2,6-difluorobenzoicacid (130A): The title compound was prepared according to the methodpresented for the synthesis of compound 75A starting with(S)-3-(2,2-difluoroethyl)morpholine.

(S)-2-(4-((S)-3-(2,2-difluoroethyl)morpholino)-2,6-difluorobenzamido)-3-(8-(1,6-dimethyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)quinolin-5-yl)propanoicacid (130): The title compound was prepared according to the methodpresented for the synthesis of compound 16A and 16 starting with 91D and130A. MS (m/z) 695.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.85 (d, J=10.4Hz, 2H), 8.72 (s, 1H), 7.65 (s, 1H), 7.52 (d, J=10.0 Hz, 1H), 6.78 (d,J=9.3 Hz, 1H), 6.46 (d, J=12.0 Hz, 2H), 6.40 (d, J=3.6 Hz, 1H), 4.67 (s,1H), 4.32 (s, 1H), 3.66 (d, J=3.2 Hz, 7H), 3.44 (s, 5H), 1.77 (s, 1H),1.55 (d, J=15.1 Hz, 1H), 0.93 (t, J=7.3 Hz, 3H).

Example 131

Synthesis of(S)-2,6-difluoro-4-(3-(2,2,2-trifluoroethyl)morpholino)benzoic acid(131A): The title compound was prepared according to the methodpresented for the synthesis of compound 75A starting with(S)-3-(2,2,2-trifluoroethyl)morpholine

(S)-2-(2,6-difluoro-4-((S)-3-(2,2,2-trifluoroethyl)morpholino)benzamido)-3-(8-(1,6-dimethyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)quinolin-5-yl)propanoicacid (131): The title compound was prepared according to the methodpresented for the synthesis of compound 16A and 16 starting with 91D and131A. MS (m/z) 713.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.90 (dd,J=7.9, 4.2 Hz, 1H), 8.86-8.77 (m, 1H), 8.65 (s, 1H), 7.63 (dd, J=8.7,4.4 Hz, 1H), 7.57 (t, J=7.1 Hz, 1H), 7.44 (dd, J=7.3, 4.5 Hz, 1H),6.66-6.50 (m, 3H), 4.78-4.66 (m, 1H), 4.28 (s, 1H), 3.89 (dd, J=11.4,3.6 Hz, 1H), 3.78 (d, J=11.9 Hz, 1H), 3.67 (dd, J=22.0, 13.3 Hz, 2H),3.57-3.36 (m, 6H), 3.07 (td, J=12.6, 3.8 Hz, 1H), 2.77 (ddd, J=15.4,11.8, 8.1 Hz, 1H), 2.53 (s, 3H), 2.39-2.20 (m, 1H).

Example 132

(S)-2-(2,6-difluoro-4-((R)-2-(trifluoromethyl)pyrrolidin-1-yl)benzamido)-3-(8-(1,6-dimethyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)quinolin-5-yl)propanoicacid (132): The title compound was prepared according to the methodpresented for the synthesis of compound 76 starting with 91D. MS (m/z)683.7 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.89 (dd, J=8.0, 3.8 Hz, 1H),8.84 (dd, J=4.3, 1.5 Hz, 1H), 8.70 (t, J=7.6 Hz, 1H), 7.71-7.63 (m, 1H),7.60 (t, J=7.5 Hz, 1H), 7.47 (dd, J=7.3, 4.1 Hz, 1H), 6.56 (t, J=1.1 Hz,1H), 6.49 (dd, J=11.3, 4.1 Hz, 2H), 4.83-4.66 (m, 2H), 3.72 (td, J=15.5,4.6 Hz, 1H), 3.58 (t, J=8.5 Hz, 1H), 3.53-3.36 (m, 4H), 3.18 (q, J=8.8Hz, 1H), 2.54 (s, 3H), 2.19-1.93 (m, 4H).

Example 133

Synthesis of 2,6-difluoro-4-(propylamino)benzoic acid (133A): The titlecompound was prepared according to the method presented for thesynthesis of compound 75A starting with propan-1-amine.

(S)-2-(2,6-difluoro-4-(propylamino)benzamido)-3-(8-(1,6-dimethyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)quinolin-5-yl)propanoicacid (133): The title compound was prepared according to the methodpresented for the synthesis of compound 16A and 16 starting with 91D and133A. MS (m/z) 603.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.82 (d, J=4.1Hz, 1H), 8.65 (dd, J=7.8, 5.4 Hz, 2H), 7.63 (dd, J=8.4, 4.1 Hz, 1H),7.60-7.53 (m, 1H), 7.44 (dd, J=7.3, 3.0 Hz, 1H), 6.55 (s, 1H), 6.15 (dd,J=11.6, 4.4 Hz, 2H), 4.74-4.61 (m, 1H), 3.78-3.61 (m, 1H), 3.49 (d,J=1.9 Hz, 3H), 3.47-3.36 (m, 1H), 2.97 (t, J=7.0 Hz, 2H), 2.53 (s, 3H),1.51 (h, J=7.3 Hz, 2H), 0.91 (t, J=7.4 Hz, 3H).

Example 134

Synthesis of (S)-4-(sec-butylamino)-2,6-difluorobenzoic acid (134A): Thetitle compound was prepared according to the method presented for thesynthesis of compound 75A starting with (S)-butan-2-amine.

(S)-2-(4-(((S)-sec-butyl)amino)-2,6-difluorobenzamido)-3-(8-(1,6-dimethyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)quinolin-5-yl)propanoicacid (134): The title compound was prepared according to the methodpresented for the synthesis of compound 16A and 16 starting with 91D and134A. MS (m/z) 617.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.86-8.77 (m,1H), 8.73-8.57 (m, 2H), 7.63 (dd, J=8.4, 4.1 Hz, 1H), 7.58 (t, J=6.4 Hz,1H), 7.48-7.40 (m, 1H), 6.55 (s, 1H), 6.33 (s, 1H), 6.15 (dd, J=11.7,4.4 Hz, 2H), 4.67 (dt, J=14.5, 5.6 Hz, 1H), 3.77-3.62 (m, 1H), 3.49 (d,J=2.0 Hz, 3H), 3.47-3.24 (m, 2H), 2.53 (s, 3H), 1.57-1.31 (m, 2H), 1.06(d, J=6.3 Hz, 3H), 0.87 (t, J=7.4 Hz, 3H).

Example 135

(S)-2-(2,6-difluoro-4-(methyl((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)-3-(8-(1,6-dimethyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)quinolin-5-yl)propanoicacid (135): The title compound was prepared according to the methodpresented for the synthesis of compound 87 starting with 91D. MS (m/z)671.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) b 8.89 (dd, J=7.9, 2.5 Hz, 1H),8.84 (dd, J=4.3, 1.5 Hz, 1H), 8.69 (s, 1H), 7.72-7.54 (m, 2H), 7.46 (dd,J=7.4, 3.3 Hz, 1H), 6.64 (dd, J=12.0, 4.4 Hz, 2H), 6.56 (d, J=1.5 Hz,1H), 5.02-4.90 (m, 1H), 4.70 (dt, J=4.7, 2.4 Hz, 1H), 3.72 (td, J=15.0,4.5 Hz, 1H), 3.54-3.35 (m, 4H), 2.82 (s, 3H), 2.54 (s, 3H), 1.38 (d,J=6.7 Hz, 3H).

Example 136

Synthesis of2,6-difluoro-4-((2R,5R)-2-methyl-5-(trifluoromethyl)morpholino)benzoicacid (136A): The title compound was prepared according to the methodpresented for the synthesis of compound 75A starting with2-methyl-5-(trifluoromethyl)morpholine. The mixture of stereoisomers wasseparated into four peaks by supercritical fluid chromatography viachiral SFC (OJ-H column) eluting with 5% TFA in EtOH to yieldintermediate 136A. The title compound was identified as the firsteluting peak.

(S)-2-(2,6-difluoro-4-((2R,5R)-2-methyl-5-(trifluoromethyl)morpholino)benzamido)-3-(8-(1,6-dimethyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)quinolin-5-yl)propanoicacid (136): The title compound was prepared according to the methodpresented for the synthesis of compound 16A and 16 starting with 91D and136A. MS (m/z) 713.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.95 (d, J=7.7Hz, 1H), 8.80 (d, J=4.1 Hz, 1H), 8.61 (d, J=8.4 Hz, 1H), 7.66-7.51 (m,2H), 7.47-7.35 (m, 1H), 6.75 (dd, J=11.5, 4.4 Hz, 2H), 6.54 (s, 1H),4.85 (s, 1H), 4.70 (s, 1H), 4.10 (s, 13H), 3.87 (d, J=12.9 Hz, 1H), 3.69(d, J=16.9 Hz, 1H), 3.49 (d, J=2.1 Hz, 3H), 3.42 (d, J=20.5 Hz, 4H),2.53 (s, 4H), 1.20 (d, J=6.6 Hz, 3H).

Example 137

Synthesis of2,6-difluoro-4-((2R,3R)-2-methyl-3-(trifluoromethyl)morpholino)benzoicacid (137A): The title compound was prepared according to the methodpresented for the synthesis of compound 75A starting with(cis)-2-methyl-3-(trifluoromethyl)morpholine. The mixture ofstereoisomers was separated into two peaks by supercritical fluidchromatography via chiral SFC (IG-H column) eluting with 10% TFA in EtOHto yield intermediate 137A. The title compound was identified as thefirst eluting peak.

(S)-2-(2,6-difluoro-4-((2R,3R)-2-methyl-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(1,6-dimethyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)quinolin-5-yl)propanoicacid (137): The title compound was prepared according to the methodpresented for the synthesis of compound 16A and 16 starting with 91D and137A. MS (m/z) 712.7 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.95 (dd,J=7.9, 3.4 Hz, 1H), 8.80 (dd, J=4.2, 1.5 Hz, 1H), 8.61 (d, J=8.7 Hz,1H), 7.65-7.52 (m, 2H), 7.48-7.38 (m, 1H), 6.74 (dd, J=11.7, 4.5 Hz,2H), 6.53 (s, 1H), 4.86 (d, J=6.9 Hz, 1H), 4.69 (td, J=9.1, 8.7, 4.3 Hz,1H), 3.94 (dd, J=11.4, 3.7 Hz, 1H), 3.85 (s, 1H), 3.48 (d, J=2.0 Hz,3H), 3.46 (s, 2H), 3.39 (dd, J=13.9, 9.6 Hz, 1H), 3.08 (dd, J=14.3, 10.6Hz, 1H), 2.52 (s, 4H), 1.34-1.24 (m, 3H).

Example 138

Synthesis of7-fluoro-5-(((2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2-yl)methyl)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline(138A): To 34C (676 mg, 1.601 mmol), bis(pinacolato)diboron (813 mg,3.202 mmol), potassium acetate (471 mg, 4.802 mmol), CataCXium A (86 mg,0.192 mmol), and tris(dibenzylideneacetone)dipalladium(0) (46 mg, 0.080mmol) were added dioxane (13.5 mL) and the reaction mixture was purgedwith N₂ for 10 min. The reaction mixture was sealed, affixed with a N₂balloon, and allowed to stir at 105° C. for 14 hrs. The reaction mixturewas cooled to RT, diluted with EA, and filtered. The filtrate wascollected and concentrated under reduced pressure to afford the titlecompound without further purification.

Synthesis of3-(7-fluoro-5-(((2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2-yl)methyl)quinolin-8-yl)-4-methoxy-1,6-dimethylpyridin-2(1H)-one(138B): To a stirred solution of 138A (325 mg, 0.277 mmol),3-bromo-4-methoxy-1,6-dimethylpyridin-2(1H)-one (128 mg, 0.554 mmol),and XPhos Pd G3 (70 mg, 0.083 mmol), in dioxane (5 mL) were added 1Mpotassium phosphate (0.96 mL, 0.989 mmol). The reaction mixture waspurged with N₂ for 5 min, sealed, and allowed to stir at 90° C. for 2hrs. The reaction mixture was concentrated under reduced pressure andpurified on silica gel chromatography eluting with Hex/EA 0-100% thenDCM/MeOH 0-30% to afford the title compound.

Synthesis of methyl(S)-2-amino-3-(7-fluoro-8-(4-methoxy-1,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)quinolin-5-yl)propanoate(138C): To a stirred solution of 138B (80 mg, 0.162 mmol) inacetonitrile (3.8 mL) was added 2M HCl (0.404 mL, 0.809 mmol). Thereaction mixture was allowed to stir at RT for 2 hrs then concentratedunder reduced pressure to yield the title compound without furtherpurification.

(S)-2-(2,6-difluoro-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)-3-(7-fluoro-8-(4-methoxy-1,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)quinolin-5-yl)propanoicacid (138): The title compound was prepared according to the methodpresented for the synthesis of compound 74 of starting with 137C. MS(m/z) 650.6 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.85 (d, J=10.4 Hz, 2H),8.72 (s, 1H), 7.65 (s, 1H), 7.52 (d, J=10.0 Hz, 1H), 6.78 (d, J=9.3 Hz,1H), 6.46 (d, J=12.0 Hz, 2H), 6.40 (d, J=3.6 Hz, 1H), 4.67 (s, 1H), 4.32(s, 1H), 3.66 (d, J=3.2 Hz, 7H), 3.44 (s, 5H), 1.77 (s, 1H), 1.55 (d,J=15.1 Hz, 1H), 0.93 (t, J=7.3 Hz, 3H).

Example 139

Synthesis of methyl(S)-3-(8-bromo-3-fluoroquinolin-5-yl)-2-(tritylamino)propanoate (139A):The title compound was prepared according to the method presented forthe synthesis of compound 91A starting with 30K.

Synthesis of methyl(S)-3-(8-bromo-3-(dimethylamino)quinolin-5-yl)-2-(tritylamino)propanoate (139B): 139A (445 mg, 0.781 mmol) was dissolved in DMF (2.4mL), and to this was added K₂CO₃ (113 mg, 0.82 mmol) and dimethylamine(4.69 mmol, 2.3 mL, 2.0M in THF). The reaction was heated to 100° C. andstirred for 21.5 hours. After cooling to RT, EA and water were added tothe reaction mixture. The aqueous layer was extracted and the organiclayer was dried over anhydrous MgSO₄, and concentrated under reducedpressure. The material was purified by silica gel chromatography using0-50% EA in hexanes to afford the title compound.

Synthesis of(S)-(3-(dimethylamino)-5-(3-methoxy-3-oxo-2-(tritylamino)propyl)quinolin-8-yl)boronic acid (139C): The title compound was preparedaccording to the method presented for the synthesis of compound 4Bstarting with 91A.

Synthesis of methyl(S)-2-amino-3-(8-(1,6-dimethyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)-3-(dimethylamino)quinolin-5-yl)propanoate(139D): The title compound was prepared according to the methodpresented for the synthesis of compound 91C and 91D in starting with139C and 3-iodo-1,6-dimethyl-4-(trifluoromethyl)pyridin-2(1H)-one.

(S)-2-(2,6-difluoro-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)-3-(8-(1,6-dimethyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)-3-(dimethylamino)quinolin-5-yl)propanoicacid (139): The title compound was prepared according to the methodpresented for the synthesis of compound 74 starting with 139D. MS (m/z)714.5 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J=7.8 Hz, 1H), 8.62(t, J=3.0 Hz, 1H), 7.58 (s, 1H), 7.44 (t, J=5.8 Hz, 1H), 7.12 (d, J=7.2Hz, 1H), 6.84-6.73 (m, 1H), 6.55 (d, J=2.7 Hz, 1H), 6.45 (dd, J=11.3,3.9 Hz, 2H), 4.67 (dt, J=13.4, 9.0 Hz, 1H), 4.31 (d, J=8.8 Hz, 1H),3.65-3.54 (m, 1H), 3.48 (d, J=1.7 Hz, 3H), 3.39-3.26 (m, 1H), 3.10 (d,J=3.9 Hz, 6H), 2.53 (s, 3H), 1.77 (ddd, J=10.7, 7.5, 3.7 Hz, 1H),1.61-1.46 (m, 1H), 0.93 (t, J=7.3 Hz, 3H).

Example 140

Synthesis of(S)-(3-fluoro-5-(3-methoxy-3-oxo-2-(tritylamino)propyl)quinolin-8-yl)boronicacid (140A): The title compound was prepared according to the methodpresented for the synthesis of compound 4B starting with 139A.

Synthesis of methyl(S)-2-amino-3-(8-(1,6-dimethyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)-3-fluoroquinolin-5-yl)propanoate(140B): The title compound was prepared according to the methodpresented for the synthesis of compound 91C and 91D in starting with140A and 3-iodo-1,6-dimethyl-4-(trifluoromethyl)pyridin-2(1H)-one.

(S)-2-(2,6-difluoro-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)-3-(8-(1,6-dimethyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)-3-fluoroquinolin-5-yl)propanoicacid (140): The title compound was prepared according to the methodpresented for the synthesis of compound 74 starting with 140B. MS (m/z)689.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.85 (d, J=2.6 Hz, 1H), 8.81(d, J=7.9 Hz, 1H), 8.37 (dt, J=10.6, 3.3 Hz, 1H), 7.60 (t, J=7.4 Hz,1H), 7.41 (dd, J=7.3, 5.2 Hz, 1H), 6.77 (d, J=9.3 Hz, 1H), 6.54 (s, 1H),6.44 (d, J=11.8 Hz, 2H), 4.68 (td, J=8.8, 4.5 Hz, 1H), 4.31 (d, J=9.1Hz, 1H), 3.62 (td, J=14.1, 4.4 Hz, 1H), 3.48 (d, J=1.7 Hz, 3H), 3.41(td, J=15.3, 9.9 Hz, 1H), 2.52 (s, 3H), 1.77 (ddd, J=13.9, 7.1, 3.3 Hz,1H), 1.52 (ddd, J=13.6, 10.2, 6.9 Hz, 1H), 0.92 (t, J=7.3 Hz, 3H).

Example 141

Synthesis of(R)-2-fluoro-6-methyl-4-(3-(trifluoromethyl)morpholino)benzoic acid(141A): The title compound was prepared according to the methodpresented for the synthesis of compound 93A starting with methyl4-bromo-2-fluoro-6-methylbenzoate.

(S)-3-(8-(1,6-dimethyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)quinolin-5-yl)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)propanoicacid (141): The title compound was prepared according to the methodpresented for the synthesis of compound 16A and 16 starting with 141Aand 91D. MS (m/z) 695.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.89-8.77(m, 2H), 8.63 (d, J=8.6 Hz, 1H), 7.68-7.53 (m, 2H), 7.43 (t, J=7.2 Hz,1H), 6.71-6.61 (m, 2H), 6.55 (d, J=3.2 Hz, 1H), 4.89-4.69 (m, 2H), 4.14(d, J=12.6 Hz, 1H), 3.94 (d, J=9.6 Hz, 1H), 3.80-3.64 (m, 2H), 3.59-3.19(m, 7H), 2.53 (s, 3H), 1.99-1.97 (m, 3H).

Example 142

Synthesis of(R)-2-fluoro-6-methyl-4-((1,1,1-trifluorobutan-2-yl)amino)benzoic acid(142A): The title compound was prepared according to the methodpresented for the synthesis of compound 74B and 74C starting with methyl4-bromo-2-fluoro-6-methylbenzoate.

(S)-3-(8-(1,6-dimethyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)quinolin-5-yl)-2-(2-fluoro-6-methyl-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)propanoicacid (142): The title compound was prepared according to the methodpresented for the synthesis of compound 16A and 16 starting with 142Aand 91D. MS (m/z) 667.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.81 (dt,J=3.9, 1.8 Hz, 1H), 8.71 (dd, J=9.9, 8.1 Hz, 1H), 8.63 (d, J=8.5 Hz,1H), 7.61 (ddd, J=20.7, 9.0, 4.6 Hz, 2H), 7.43 (t, J=6.8 Hz, 1H), 6.55(d, J=3.5 Hz, 1H), 6.41-6.34 (m, 2H), 6.28 (d, J=9.2 Hz, 1H), 4.80-4.67(m, 1H), 4.18 (br s, 1H), 3.71 (ddd, J=28.0, 14.6, 4.0 Hz, 1H),3.53-3.29 (m, 4H), 2.53 (s, 3H), 1.95-1.91 (m, 3H), 1.80-1.70 (m, 1H),1.59-1.47 (m, 1H), 0.96-0.87 (m, 3H).

Example 143

Synthesis of(R)-2,6-dichloro-4-((1,1,1-trifluorobutan-2-yl)amino)benzoic acid(143A): The title compound was prepared according to the methodpresented for the synthesis of compound 74B and 74C starting withtert-butyl 4-bromo-2,6-dichlorobenzoate.

(S)-2-(2,6-dichloro-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)-3-(8-(1,6-dimethyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)quinolin-5-yl)propanoicacid (143): The title compound was prepared according to the methodpresented for the synthesis of compound 16A and 16 starting with 143Aand 91D. MS (m/z) 703.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.01 (dd,J=26.1, 8.3 Hz, 1H), 8.82 (d, J=3.5 Hz, 1H), 8.66 (d, J=8.6 Hz, 1H),7.65 (dd, J=18.5, 9.6 Hz, 2H), 7.43 (dd, J=7.4, 3.8 Hz, 1H), 6.77 (s,1H), 6.55 (q, J=5.9 Hz, 2H), 4.85-4.63 (m, 1H), 4.33 (s, 1H), 3.69 (ddd,J=19.3, 14.5, 4.0 Hz, 1H), 3.49 (d, J=4.0 Hz, 3H), 3.42-3.31 (m, 1H),2.53 (s, 3H), 1.85-1.60 (m, 1H), 1.51 (dt, J=11.8, 7.9 Hz, 1H), 0.93(td, J=7.3, 3.0 Hz, 3H).

Example 144

Synthesis of(R)-2-chloro-6-fluoro-4-((1,1,1-trifluorobutan-2-yl)amino)benzoic acid(144A): The title compound was prepared according to the methodpresented for the synthesis of compound 74B and 74C starting withtert-butyl 4-bromo-2-chloro-6-fluorobenzoate.

(S)-2-(2-chloro-6-fluoro-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)-3-(8-(1,6-dimethyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)quinolin-5-yl)propanoicacid (144): The title compound was prepared according to the methodpresented for the synthesis of compound 16A and 16 starting with 144Aand 91D. MS (m/z) 687.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.97 (dd,J=12.0, 8.1 Hz, 1H), 8.82 (s, 1H), 8.65 (s, 1H), 7.69-7.54 (m, 2H), 7.43(d, J=6.2 Hz, 1H), 6.67-6.61 (m, 2H), 6.61-6.51 (m, 2H), 4.71 (dd,J=23.5, 11.8 Hz, 1H), 4.31 (s, 1H), 3.76-3.63 (m, 1H), 3.49 (d, J=3.4Hz, 3H), 3.48-3.28 (m, 1H), 2.53 (s, 3H), 1.75 (d, J=8.3 Hz, 1H),1.66-1.46 (m, 1H), 1.01-0.88 (m, 3H).

Example 145

Synthesis of tert-butyl(R)-2-fluoro-5-methyl-4-((1,1,1-trifluorobutan-2-yl)amino) benzoate(145B): The title compound was prepared according to the methodpresented for the synthesis of compound 74B and 74C starting withtert-butyl 4-bromo-2-fluoro-5-methylbenzoate.

(S)-3-(8-(1,6-dimethyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)quinolin-5-yl)-2-(2-fluoro-5-methyl-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)propanoicacid (145): The title compound was prepared according to the methodpresented for the synthesis of compound 16A and 16 starting with 145Band 91D. MS (m/z) 667.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d,J=4.0 Hz, 1H), 8.75 (t, J=11.1 Hz, 1H), 7.94 (d, J=7.2 Hz, 1H), 7.60(dd, J=24.9, 7.1 Hz, 2H), 7.53-7.41 (m, 1H), 7.36-7.18 (m, 1H),6.76-6.61 (m, 1H), 6.55 (s, 1H), 5.52 (d, J=8.6 Hz, 1H), 4.78 (s, 1H),4.38 (s, 1H), 3.73 (t, J=13.5 Hz, 1H), 3.59 (dd, J=15.9, 9.6 Hz, 1H),3.53-3.41 (m, 3H), 2.53 (d, J=2.3 Hz, 3H), 2.10 (t, J=2.9 Hz, 3H),1.96-1.62 (m, 2H), 0.98-0.82 (m, 3H).

Example 146

Synthesis of(R)-3-bromo-2,6-difluoro-4-((1,1,1-trifluorobutan-2-yl)amino)benzoicacid (146A). To stirred solution of 74C (216 mg, 0.76 mmol) indichloroethane (4 mL) was added TFA (0.292 mL, 3.8 mmol), andN-bromosuccinimide (143 mg, 0.80 mmol) and the mixture was heated to 50°C. After 1h the mixture was added to silica gel and chromatographedeluting with ethyl acetate in hexanes to the title compound.

Synthesis of (trimethylsilyl)methyl2,6-difluoro-3-((E)-3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-en-1-yl)-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzoate(146B). To a microwave vial was added 146A (230 mg, 0.635 mmol), dioxane(4 mL), (Trimethylsilyl)diazomethane solution (1N ether) (0.635 mL,0.635 mmol), potassium carbonate (176 mg, 1.3 mmol) palladium tetrakistriphenylphosphine (73.4 mg, 0.06 mmol), and(E)-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-en-1-yl)boronic acid(236.31 mg, 1.27 mmol). The vessel was sealed and heated to 110° C. for35 minutes. The mixture was then added to silica gel and chromatographedeluting with ethyl acetate in hexanes to afford the title compound.

Synthesis of (trimethylsilyl)methyl(R)-2,6-difluoro-3-(3-hydroxypropyl)-4-((1,1,1-trifluorobutan-2-yl)amino)benzoate(146C). 146B (160 mg, 0.314 mmol), was added to a Parr shaker bottlewith 5% palladium on charcoal (25 mg) and the mixture was shakenovernight under 50 PSI of H2. The mixture was filtered and HCl inmethanol was added (9 mL, 3N) and the mixture was stirred for 4h.Volatile components of the mixture were removed on a rotary evaporator,dissolved in DCM, washed with sodium bicarbonate (aq) and the residuewas chromatographed on silica gel eluting with methanol in DCM to affordthe title compound.

Synthesis of (trimethylsilyl)methyl(R)-5,7-difluoro-1-(1,1,1-trifluorobutan-2-yl)-1,2,3,4-tetrahydroquinoline-6-carboxylate(146D). To a stirred solution of 146C (107 mg, 0.215 mmol), and TEA (0.1ml, 0.9 mmol) in DCM (1 mL) was added methanesulfonyl chloride (39 uL,0.5 mmol) and let stir for ten minutes. The mixture was washed withsodium bicarbonate (aq) and the volatile components of the organic layerwere removed on a rotary evaporator and diluted with THF (2 mL) andpotassium carbonate was added (173 mg, 1.25 mmol) and the mixture washeated to 70° C. overnight. The mixture was chromatographed on silicagel eluting with ethyl acetate in hexanes to afford the title compound.

Synthesis of(R)-5,7-difluoro-1-(1,1,1-trifluorobutan-2-yl)-1,2,3,4-tetrahydroquinoline-6-carboxylicacid (146E). To 146D (95 mg, 0.2 mmol) was added methanol (10 mL) andlithium hydroxide (4 mg) and water (2 mL) and the mixture was stirredover the weekend at 85° C. The mixture was neutralized with HCl indioxane and the solvents were removed on a rotary evaporator. The titlecompound thus obtained was used without further purification.

(S)-2-(5,7-difluoro-1-((R)-1,1,1-trifluorobutan-2-yl)-1,2,3,4-tetrahydroquinoline-6-carboxamido)-3-(8-(1,6-dimethyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)quinolin-5-yl)propanoicacid (146): The title compound was prepared according to the methodpresented for the synthesis of compound 16A and 16 starting with 91D and146E. MS (m/z) 711.3 [M+H]+. 1H NMR (400 MHz, Chloroform-d) δ 9.30 (dd,J=86.9, 8.7 Hz, 1H), 7.87-7.50 (m, 3H), 7.00 (d, J=35.4 Hz, 1H), 6.53(d, J=12.4 Hz, 1H), 6.24 (dd, J=14.4, 6.2 Hz, 1H), 5.00 (dd, J=29.5, 6.2Hz, 1H), 4.22-3.85 (m, 1H), 3.89-3.64 (m, 1H), 3.56 (d, J=7.5 Hz, 3H),3.25 (s, 2H), 2.74-2.61 (m, 2H), 2.10-1.66 (m, 4H), 0.95 (t, J=7.4 Hz,3H).

Example 147

Preparation of(S)-2-(2,6-difluoro-4-(((R)-1,1,1-trifluorobutan-2-yl)amino)benzamido)-3-(8-(1,6-dimethyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)quinolin-5-yl)propanoicacid (147): 91 was separated into its 2 atropisomeric enantiomers bysupercritical fluid chromatography using 30% MeOH co-solvent, at a flowrate of 60 mL/min, using an IC 5 μm 21×250 mm column. The title compoundwas identified as the second eluting peak. MS (m/z) 671.2 [M+H]⁺. 1H NMR(400 MHz, DMSO-d6) δ 8.82 (t, J=6.4 Hz, 2H), 8.67 (d, J=8.7 Hz, 1H),7.70-7.50 (m, 2H), 7.45 (d, J=7.3 Hz, 1H), 6.76 (d, J=9.3 Hz, 1H), 6.55(s, 1H), 6.43 (d, J=11.9 Hz, 2H), 4.68 (m, 1H), 4.37-4.24 (m, 1H),3.67-3.63 (m, 1H), 3.48 (m, 4H), 2.52 (s, 3H), 1.74 (m, 1H), 1.53 (m,1H), 0.91 (t, J=7.4 Hz, 3H).

Example 148

Preparation of(S)-3-(8-(2-chloro-4-cyanophenyl)quinolin-5-yl)-2-(2,6-difluoro-4-((R)-3-(trifluoromethyl)morpholino)benzamido)propanoicacid (148): 89 was separated into its 2 enantiomers by supercriticalfluid chromatography using 30% EtOH/TFA co-solvent, at a flow rate of 45mL/min, using an IE 5 μm 21×250 mm column. The title compound wasidentified as the second eluting peak. MS (m/z) 629.2 [M+H]⁺. 1H NMR(400 MHz, DMSO-d6) δ 8.86-8.75 (m, 2H), 8.63 (dd, J=8.6, 1.6 Hz, 1H),8.15 (dd, J=1.6, 0.4 Hz, 1H), 7.89 (dd, J=7.9, 1.7 Hz, 1H), 7.66-7.51(m, 4H), 6.92 (d, J=9.4 Hz, 1H), 6.40 (d, J=11.8 Hz, 2H), 4.67 (s, 1H),3.97-3.89 (m, 1H), 3.72 (s, 1H), 3.40 (s, 1H), 1.03 (ddt, J=13.0, 8.1,4.2 Hz, 1H), 0.66-0.55 (m, 1H), 0.55-0.43 (m, 2H), 0.30 (dd, J=9.7, 4.9Hz, 1H).

Example 355

Synthesis of methyl(S)-3-(8-((diphenylmethylene)amino)quinolin-5-yl)-2-(tritylamino)propanoate(355A): To a flame-dried 200 mL flask equipped with a stir bar was added2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (Binap ligand) (1.26 g,2.029 mmol, 0.10 eq) in dioxane (101 mL, 0.2 M) and the flask was vacuumpurged then flushed with N₂ 3 times. Bis(dibenzylideneacetone)palladium(Palladium dba) (0.93 g, 1.015 mmol, 0.05 eq) was added and the reactionwas allowed to stir at room temperature for 10 minutes. Cesium carbonate(19.83 g, 60.87 mmol, 3 eq.), benzophenone imine (6.81 mL, 40.58 mmol, 2eq.), and methyl (S)-3-(8-bromoquinolin-5-yl)-2-(tritylamino)propanoate(91A) (11.19 g, 20.29 mmol, 1 eq.) were added and the reaction washeated to 100° C. under a N₂ balloon and stirred overnight. The reactionwas cooled to room temperature and quenched by the addition of water(100 mL). The reaction mixture was then extracted with ethyl acetate(100 mL, 3×), the combined organic phases were washed with brine (100mL) and dry packed onto silica gel. Purification was performed viasilica gel chromatography eluting with 20% EtOAc in hexanes until excessbenzophenone imine was eluted (˜20 min), then the percentage of EtOAcwas increased to 25% in hexanes to elute product. Product containingfractions were concentrated under vacuum.

Synthesis of methyl(S)-3-(8-aminoquinolin-5-yl)-2-(tritylamino)propanoate (355B): 355A(11.19 g, 17.17 mmol, 1 eq.) was dissolved in THF (100 mL) to which wasadded hydroxylamine HCl (4.77 g, 68.67 mmol, 4 eq.), and sodium acetatetrihydrate (14.02 g, 103.01 mmol, 6 eq.). MeOH (50 mL) was added and thereaction was allowed to stir at room temperature for 3 h. The reactionmixture was concentrated under vacuum and absorbed onto pre-packedsilica gel. Purification was performed via silica gel chromatographyusing 20% EtOAc in Hexanes until excess hydroxyl-imine was eluted (˜20min), then the percentage of EtOAc was increased to 25% in hexanes toelute product. Product containing fractions were concentrated undervacuum.

Synthesis of methyl(S)-3-(3-(5-(3-methoxy-3-oxo-2-(tritylamino)propyl)quinolin-8-yl)ureido)isonicotinate(355C): To a flame-dried flask equipped with a stir bar was added4-methoxycarbonylpyridine-3-carboxylic acid (0.22 g, 1.23 mmol, 1.2eq.), triethylamine (0.43 ml, 3.08 mmol, 3 eq.), DPPA (0.24 mL, 1.13mmol, 1.1 eq.), 355B, and toluene (5.12 mL, 0.2 M). The reaction wasaffixed with a condenser (open to atmosphere) and heated to 50° C. for 2h. The reaction was quenched with water (50 mL) and extracted with EtOAc(50 mL, 3×). The combined organic phases were washed with sat. sodiumbicarbonate (25 mL), brine, and dried over anhydrous Na₂SO₄. Organicphases were concentrated and used without further purification.

Synthesis of methyl(S)-3-(8-(2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)quinolin-5-yl)-2-(tritylamino)propanoate(355D): 355C (0.68 g, 1.03 mmol, 1.0 eq.) was dissolved in THF (4 mL)and MeOH (4 mL), to which was added solid potassium carbonate (0.71 g,5.13 mmol, 5 eq.). The reaction mixture was allowed to stir 1 h at roomtemperature. The reaction was diluted with water and sat. NH₄Cl (4 mL),extracted with EtOAc (20 mL, 3×), washed with brine, and dried overNa₂SO₄. The combined organic phases were concentrated, EtOAc (˜10 mL)was added, then hexanes was added dropwise under stirring to form aprecipitate. The filtrate was collected and dried under high vacuum.

Synthesis of methyl(S)-3-(8-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)quinolin-5-yl)-2-(tritylamino)propanoate(355E): To a flame-dried flask was added Intermediate 355D (4.05 g,6.396 mmol, 1.0 eq.), potassium carbonate (0.88 g, 6.4 mmol, 1.0 eq.)and DMF (32 mL, 0.2 M). The reaction mixture was stirred for 10 minutesat room temperature, then methyl tosylate (0.97 mL, 6.4 mmol, 1.0 eq.)was added and the reaction was allowed to stir overnight at roomtemperature. The reaction was concentrated and purified via silica gelchromatography eluting with DCM/MeOH 0-5%.

Synthesis of methyl (S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)quinolin-5-yl)propanoate(355): 355E (1.49 g, 2.29 mmol, 1 eq.) was dissolved in DCM (51 mL) andtriethylsilane (0.44 mL, 2.75 mmol, 1.2 eq.), and TFA (0.53 ml, 6.88mmol, 3 eq.) were added. The reaction mixture was allowed to stir atroom temperature for 2 h, then concentrated. The resulting material wasre-suspended in DCM and concentrated again under vacuum to removeresidual TFA. The material was used without further purification. Theresulting material (1.47 g, 2.31 mmol, 1.0 eq.), 141A (0.85 g, 2.78mmol, 1.2 eq.), and HATU (1.06 g, 2.78 mmol, 1.2 eq.) were added to avial and dissolved in DMF (10 mL). DIEA (2.42 mL, 13.89 mmol, 6.0 eq.)was added and the reaction was allowed to stir at room temperature for 2h. The reaction was quenched with water and extracted with EtOAc,organic phases were washed with brine, and dried over Na₂SO₄. Theorganic phases were concentrated and purified via silica gelchromatography using DCM/MeOH 0-5%. ES/MS m/z [M+H]: 695.198; 1H NMR(400 MHz, DMSO-d6) δ 9.05 (s, 1H), 8.95-8.80 (m, 2H), 8.71 (dd, J=8.7,1.6 Hz, 1H), 8.60 (dd, J=4.9, 1.4 Hz, 1H), 7.92 (ddd, J=4.8, 3.8, 0.7Hz, 1H), 7.77 (d, J=7.6 Hz, 1H), 7.75-7.63 (m, 2H), 6.73-6.63 (m, 2H),4.90-4.72 (m, 2H), 4.14 (d, J=12.6 Hz, 1H), 3.94 (dd, J=11.4, 3.6 Hz,1H), 3.83-3.69 (m, 3H), 3.66 (d, J=2.5 Hz, 3H), 3.51 (ddd, J=25.5, 13.6,9.8 Hz, 2H), 3.35 (d, J=12.2 Hz, 1H), 3.26 (d, J=12.3 Hz, 1H), 2.09-1.95(m, 3H).

Example 356

(S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)quinolin-5-yl)propanoicacid (356): 355 (0.49 g, 0.70 mmol, 1.0 eq.) was dissolved in THF (10mL) and 1M LiOH (3.5 ml, 5 eq.) was added. The reaction mixture wasallowed to stir at room temperature for 2 h. 4 M HCl in dioxane (1.75mL, 10 eq.) was then added to re-cyclize, and the reaction mixture wasallowed to stir for 1 h. The reaction was concentrated and purified viareverse phase HPLC, lyophilized to afford the title compound as amono-TFA salt. ES/MS (m/z) [M+H]: 681.151 1H NMR (400 MHz, DMSO-d6) δ9.05 (s, 1H), 8.92-8.77 (m, 2H), 8.68 (d, J=8.6 Hz, 1H), 8.60 (d, J=5.0Hz, 1H), 7.91 (t, J=4.3 Hz, 1H), 7.76 (d, J=7.6 Hz, 1H), 7.67 (dd,J=8.3, 4.5 Hz, 2H), 6.74-6.58 (m, 2H), 5.00-4.59 (m, 2H), 4.14 (d,J=12.6 Hz, 1H), 3.99-3.91 (m, 1H), 3.66 (d, J=2.4 Hz, 4H), 3.59-3.40 (m,1H), 3.31 (dd, J=35.1, 12.3 Hz, 3H), 2.03 (s, 3H).

Example 357

(((S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)quinolin-5-yl)propanoyl)oxy)methylpivalate (357): 356 (611 mg, 0.898 mmol) was dissolved in acetonitrile(44 mL), and added iodomethyl 2,2-dimethylpropanoate (434.6 mg, 1.8mmol), and N,N-diisopropylethylamine (0.31 mL, 2 mmol) and stirred for 1h. Solvents were removed on a rotary evaporator and the mixture wasreverse phase chromatographed to provide the title compound as a TFAsalt. ES/MS (m/z) 735.063 [M+H]; 1H NMR (400 MHz, DMSO-d6) δ 9.15-9.00(m, 2H), 8.85 (d, J=3.9 Hz, 1H), 8.67-8.57 (m, 2H), 7.91 (ddd, J=5.0,3.1, 0.8 Hz, 1H), 7.76 (d, J=7.5 Hz, 1H), 7.73-7.61 (m, 2H), 5.83 (s,2H), 4.85 (d, J=9.2 Hz, 2H), 4.14 (d, J=12.6 Hz, 1H), 4.06-3.88 (m, 1H),3.84-3.68 (m, 2H), 3.65 (d, J=2.2 Hz, 3H), 3.53 (dt, J=14.8, 9.7 Hz,2H), 3.36 (d, J=12.3 Hz, 1H), 3.26 (d, J=12.1 Hz, 1H), 2.03 (s, 3H),1.18 (s, 9H).

Example 358

2-(Diethylamino)ethyl(S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)quinolin-5-yl)propanoate(358): To 356 (45 mg, 0.066 mmol), was added THF (3 mL),2-(diethylamino)ethanol (23.24 mg, 0.2 mmol), triphenyl phosphine (0.05g, 0.2 mmol), diethyl azodicarboxylate, 95% (0.1 ml, 0.2 mmol), and DIEA(0.41 ml, 2.28 mmol). The mixture was stirred for 1 h, then solventswere removed on a rotary evaporator, and the mixture was reverse phasechromatographed to provide the title compound as a TFA salt afterlyophilization. ES/MS (m/z) 780.300 [M+H]; 1H NMR (400 MHz,Chloroform-d) δ 9.28 (dt, J=4.8, 1.6 Hz, 1H), 9.20 (ddd, J=8.7, 4.6, 1.5Hz, 1H), 8.90 (d, J=2.2 Hz, 1H), 8.62 (dd, J=5.0, 1.6 Hz, 1H), 8.04 (dd,J=24.7, 5.0 Hz, 1H), 7.83 (dd, J=8.6, 4.7 Hz, 1H), 7.75 (d, J=1.2 Hz,2H), 7.46 (d, J=7.0 Hz, 1H), 6.49 (d, J=2.4 Hz, 1H), 6.43-6.27 (m, 1H),5.18 (q, J=7.6 Hz, 1H), 4.97 (dd, J=12.8, 6.4 Hz, 1H), 4.53 (td, J=9.2,7.8, 4.6 Hz, 1H), 4.31 (d, J=12.4 Hz, 1H), 4.16 (ddt, J=19.3, 8.0, 3.3Hz, 1H), 4.10-3.90 (m, 2H), 3.82 (dd, J=12.5, 2.2 Hz, 1H), 3.72 (d,J=9.4 Hz, 3H), 3.60 (ddt, J=32.1, 17.2, 8.3 Hz, 3H), 3.28 (d, J=12.0 Hz,1H), 3.22-3.09 (m, 1H), 3.03 (s, 4H), 2.32 (s, 3H), 1.49-1.10 (m, 9H),1.02 (d, J=7.6 Hz, 2H).

Example 359

Phenyl (S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)quinolin-5-yl)propanoate(359): 356 (567 mg, 0.833 mmol) was dissolved in THF (5 mL), phenol(0.12 g, 1.25 mmol), TBTU (0.4 g, 1.25 mmol), DIEA (0.44 mL, 2.5 mmol),and DMAP (0.1 g, 0.83 mmol) were added, and the reaction mixture wasstirred for 1 h. The reaction mixture was then loaded directly ontosilica and chromatographed eluting with ethylacetate in methanol (0-10%)to provide the title compound. ES/MS (m/z) 757.213 [M+H]; 1H NMR (400MHz, DMSO-d6) b 9.22 (d, J=7.1 Hz, 1H), 9.05 (s, 1H), 8.89-8.83 (m, 1H),8.76 (d, J=8.6 Hz, 1H), 8.61 (d, J=5.0 Hz, 1H), 7.93 (d, J=5.0 Hz, 1H),7.85-7.77 (m, 1H), 7.77-7.71 (m, 1H), 7.71-7.64 (m, 1H), 7.48-7.38 (m,2H), 7.31-7.23 (m, 1H), 7.10-7.01 (m, 2H), 6.77-6.69 (m, 1H), 6.68 (s,1H), 5.09-4.99 (m, 1H), 4.91-4.79 (m, 1H), 4.15 (d, J=12.7 Hz, 1H),4.00-3.89 (m, 1H), 3.89-3.82 (m, 2H), 3.67 (s, 3H), 3.61-3.49 (m, 2H),3.43-3.32 (m, 1H), 3.32-3.19 (m, 1H), 2.15-2.05 (m, 3H).

Example 360

Ethyl(S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)quinolin-5-yl)propanoate(360): To a solution of 356 (150 mg, 0.22 mmol) in DMF (1.0 mL) wasadded triphenylphosphine (173 mg, 0.66 mmol) followed by DIEA (117 μL,0.66 mmol) and ethanol (129 μL. 2.2 mmol). DIAD (217 μL, 1.1 mmol) wasthen added and the reaction mixture was allowed to stir for 2 hours. Thereaction mixture was then diluted with EtOAc and washed with water, 10%citric acid, saturated sodium bicarbonate, and brine followed by dryingthe combined organics over sodium sulfate. After filtration, the solventwas removed under reduced pressure and the product was purified bynormal phase using an elution gradient of 0-30%, 30-60%, and 60-100% 9:1DCM:MeOH in DCM. ES/MS (m/z) [M+H]: 709.2. 1H NMR (400 MHz, DMSO-d6) δ9.04 (s, 1H), 8.99 (d, J=7.7 Hz, 1H), 8.84 (dd, J=4.2, 1.4 Hz, 1H), 8.64(dd, J=8.7, 1.6 Hz, 1H), 8.60 (d, J=4.9 Hz, 1H), 7.91 (dd, J=5.0, 2.2Hz, 1H), 7.75 (d, J=7.5 Hz, 1H), 7.66 (dt, J=8.6, 2.5 Hz, 2H), 6.76-6.63(m, 2H), 4.82 (td, J=14.4, 12.1, 5.3 Hz, 2H), 4.20-4.04 (m, 3H), 3.95(dd, J=11.5, 3.6 Hz, 1H), 3.80-3.66 (m, 2H), 3.65 (d, J=1.6 Hz, 3H),3.60-3.46 (m, 2H), 3.36 (d, J=13.7 Hz, 1H), 3.31-3.18 (m, 1H), 2.07 (s,3H), 1.16 (td, J=7.1, 1.1 Hz, 3H).

Example 361

1-((Ethoxycarbonyl)oxy)ethyl(2S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)quinolin-5-yl)propanoate(361): To a solution of 356 (30 mg, 0.044 mmol) in DMF (1 mL) was addedpotassium carbonate (8.2 mg, 0.132 mmol), followed by sodium iodide (26mg, 0.176 mmol) and 1-chloroethyl ethyl carbonate (20 mg, 0.132 mmol).The reaction mixture was heated to 65° C. for 2 h. Then the reactionmixture was cooled to RT and filtered. The resulting filtrate waspurified by reverse phase HPLC to yield the title compound as a TFAsalt. ES/MS (m/z) [M+H]: 797.2 1H NMR (400 MHz, DMSO-d6) δ 9.05 (d,J=5.5 Hz, 2H), 8.90-8.81 (m, 1H), 8.70-8.57 (m, 2H), 7.91 (d, J=5.1 Hz,1H), 7.76 (d, J=7.6 Hz, 1H), 7.67 (d, J=7.9 Hz, 2H), 6.74-6.64 (m, 2H),4.86 (s, 2H), 4.35-4.06 (m, 3H), 3.95 (d, J=11.0 Hz, 1H), 3.74 (d,J=13.2 Hz, 6H), 3.53 (q, J=14.3, 13.3 Hz, 2H), 3.42-3.13 (m, 2H), 2.03(d, J=20.9 Hz, 3H), 1.53 (d, J=5.4 Hz, 1H), 1.38 (d, J=5.4 Hz, 2H), 1.23(t, J=7.1 Hz, 3H).

Example 362

(R)-tetrahydrofuran-2-yl)methyl(S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)quinolin-5-yl)propanoate(362): 356 (0.52 g, 0.76 mmol) was dissolved in DMF (3 mL), andtriphenylphosphine (0.6 g, 2.28 mmol), diisopropyl azodicarboxylate(0.46 mL, 2.28 mmol), (2R)-tetrahydrofuran-2-yl]methanol (0.23 g, 2.28mmol), and diisopropylethylamine (0.41 ml, 2.28 mmol) were added. Themixture was stirred for 1 h and chromatographed on silica gel elutingwith ethyl acetate and methanol (0-10%) to provide the title compound.ES/MS (m/z) 735.063 [M+H]; 1H NMR (400 MHz, DMSO-d6) δ 9.02 (d, J=7.5Hz, 1H), 6.88 (d, J=7.6 Hz, 1H), 6.80 (d, J=11.8 Hz, 3H), 5.05-4.84 (m,1H), 4.58 (q, J=7.5, 6.9 Hz, 1H), 4.17 (d, J=12.7 Hz, 1H), 4.09-3.92 (m,7H), 3.74 (q, J=6.0 Hz, 2H), 3.70-3.54 (m, 2H), 3.24 (t, J=12.5 Hz, 1H),3.10 (dd, J=14.5, 5.1 Hz, 1H), 2.96 (dd, J=14.4, 9.3 Hz, 1H), 2.76 (d,J=5.3 Hz, 2H), 2.32 (s, 3H), 2.26 (s, 3H), 1.86 (ddq, J=40.9, 13.8, 6.4Hz, 6H), 1.57 (q, J=8.7, 8.1 Hz, 1H), 1.26 (d, J=12.8 Hz, 2H), 0.97-0.74(m, 2H).

Example 363

Cyclopropyl (S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)quinolin-5-yl)propanoate(363): To a solution of 356 (0.650 g, 0.955 mmol) in THF (4.80 mL) wasadded cyclopropyl alcohol (0.166 g, 2.87 mmol), DMAP (0.117 g, 0.955mmol), DIEA (0.370 g, 2.87 mmol), and TBTU (0.920 g, 2.87 mmol) and themixture was stirred at 50° C. for 25 min. Upon completion, the reactionmixture was diluted with EtOAc, and washed with water (×2). The organiclayer was then concentrated under reduced pressure and the residue waspurified using flash chromatography eluting with EtOAc in hexanes0-100%, followed by MeOH in EtOAc 0-50%. Appropriate fractions werecombined and concentrated to afford the product. The product was thendissolved in DMSO (12 mL) and purified using reverse phase HPLC toafford the title compound. ES/MS (m/z) 721.3 [M+H]; 1H NMR (400 MHz,DMSO-d6) δ 9.04 (s, 1H), 8.98 (d, J=7.6 Hz, 1H), 8.83 (d, J=4.2 Hz, 1H),8.61 (dd, J=11.5, 6.8 Hz, 2H), 7.91 (d, J=4.9 Hz, 1H), 7.75 (d, J=7.6Hz, 1H), 7.72-7.59 (m, 2H), 6.79-6.61 (m, 2H), 4.79 (dd, J=21.2, 12.1Hz, 2H), 4.22-4.05 (m, 2H), 4.05-3.87 (m, 1H), 3.80-3.43 (m, 7H),3.42-3.21 (m, 4H), 3.21-3.10 (m, 1H), 2.69 (d, J=1.3 Hz, 1H), 2.05 (d,J=7.2 Hz, 3H), 0.80-0.48 (m, 3H).

Example 364

2-(2-Methyl-1H-imidazol-1-yl)ethyl(S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)quinolin-5-yl)propanoate(364): To a stirred solution of 356 (438.6 mg, 0.64 mmol) and1-(2-chloroethyl)-2-methyl-1H-imidazole (279.6 mg, 1.93 mmol) in DMF(4.3 mL) was added sodium iodide (289.8 mg, 1.93 mmol), followed bytriethylamine (0.27 mL, 1.93 mmol). The reaction mixture was heatedusing microwave irradiation at 120° C. for 45 minutes. After cooling toRT, the reaction was concentrated under reduced pressure and thematerial was purified using reverse phase prep HPLC to afford the titlecompound. MS (m/z) 789.3 [M+H]⁺. 1H NMR (400 MHz, DMSO-d6) δ 9.04 (d,J=8.2 Hz, 2H), 8.87 (d, J=4.1 Hz, 1H), 8.64-8.57 (m, 2H), 7.91 (t, J=4.8Hz, 1H), 7.77 (d, 1H), 7.71-7.59 (m, 3H), 7.56 (s, 1H), 6.74-6.65 (m,2H), 4.90-4.76 (m, 2H), 4.52-4.42 (m, 1H), 4.41-4.28 (m, 3H), 4.15 (d,J=12.6 Hz, 1H), 3.94 (d, J=3.5 Hz, 1H), 3.73 (d, J=12.7 Hz, 1H),3.69-3.60 (m, 4H), 3.59-3.47 (m, 2H), 3.34 (d, 1H), 3.25 (t, 1H), 2.53(s, 3H), 2.03 (s, 3H).

Example 365

Propyl (S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)quinolin-5-yl)propanoate(365): To a stirred solution of 356 (30 mg, 0.044 mmol) in acetonitrile(1 mL) was added cesium carbonate (72 mg, 0.22 mmol) and n-propyl iodide(15 mg, 0.088 mmol). The mixture was heated to 50° C. for 16 hours. Themixture was cooled to ambient temperature, diluted withdimethylsulfoxide and trifluoroacetic acid, then the mixture waspurified by preparatory HPLC to yield the title compound. ES/MS (m/z)723.3 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 9.05 (s, 1H), 8.99 (d, J=7.8Hz, 1H), 8.84 (d, J=4.2 Hz, 1H), 8.66 (d, J=8.6 Hz, 1H), 8.60 (d, J=5.1Hz, 1H), 7.91 (dd, J=4.9, 2.4 Hz, 1H), 7.76 (d, J=7.5 Hz, 1H), 7.67 (dd,J=8.0, 2.7 Hz, 2H), 6.71 (dd, J=13.7, 5.1 Hz, 1H), 6.66 (s, 1H), 4.85(s, 2H), 4.15 (d, J=12.6 Hz, 1H), 4.05 (q, J=6.3 Hz, 2H), 4.00-3.89 (m,1H), 3.73 (d, J=13.5 Hz, 2H), 3.66 (s, 3H), 3.54 (t, J=7.7 Hz, 2H), 3.36(d, J=12.4 Hz, 1H), 3.25 (t, J=12.1 Hz, 1H), 2.05 (d, J=6.8 Hz, 3H),1.58 (h, J=7.2 Hz, 2H), 0.88 (t, J=7.4 Hz, 3H).

Example 366

Isopropyl(S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)quinolin-5-yl)propanoate(366): To a stirred solution of 356 (30 mg, 0.044 mmol) in acetonitrile(1 mL) was added cesium carbonate (72 mg, 0.22 mmol) and isopropyliodide (15 mg, 0.088 mmol). The mixture was heated to 50° C. for 16hours. The mixture was cooled to ambient temperature, diluted withdimethylsulfoxide and trifluoroacetic acid, then the mixture waspurified by preparatory HPLC to yield 366. ES/MS (m/z) 723.3 (M+H)+. 1HNMR (400 MHz, DMSO-d6) δ 9.05 (s, 1H), 8.97 (d, J=7.7 Hz, 1H), 8.84 (d,J=4.1 Hz, 1H), 8.65 (d, J=8.7 Hz, 1H), 8.60 (d, J=5.0 Hz, 1H), 7.91 (d,J=5.0 Hz, 1H), 7.76 (d, J=7.5 Hz, 1H), 7.71-7.62 (m, 2H), 6.71 (d,J=13.1 Hz, 1H), 6.68-6.63 (m, 1H), 4.97-4.90 (m, 1H), 4.84 (dd, J=29.2,20.4 Hz, 2H), 4.15 (d, J=12.7 Hz, 1H), 3.95 (d, J=11.3 Hz, 1H), 3.73 (d,J=13.7 Hz, 2H), 3.66 (s, 3H), 3.53 (q, J=13.5, 11.7 Hz, 2H), 3.36 (d,J=12.3 Hz, 1H), 3.27 (d, J=12.5 Hz, 1H), 2.08 (d, J=6.7 Hz, 3H), 1.22(d, J=6.2 Hz, 3H), 1.13 (d, J=6.3 Hz, 3H).

Example 398

Synthesis of Methyl(S)-3-(3-(5-(3-methoxy-3-oxo-2-(tritylamino)propyl)quinolin-8-yl)ureido)picolinate(398A): To a vial was added 355B (50 mg, 0.1 mmol), 2-methoxycarbonylpyridine-3-carboxylic acid (27.86 mg, 0.15 mmol), triethylamine (0.04mL, 0.31 mmol), and dissolved in 0.2 M toluene (0.51 ml). DPPA (0.03 mL,0.12 mmol) was added and reaction mixture was sealed and heated to 90°C. for 20 min. The reaction was quenched with water (20 mL), extractedwith EtOAc (3×40 mL), organic phases were washed with brine (20 mL), andconcentrated to afford the title compound.

Synthesis of methyl(S)-3-(8-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,2-d]pyrimidin-3(2H)-yl)quinolin-5-yl)-2-(tritylamino)propanoate(398B): The title compound was prepared according to the methodpresented for the synthesis of compound 355E, starting with 398A.

Methyl (S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,2-d]pyrimidin-3(2H)-yl)quinolin-5-yl)propanoate(398): The title compound was prepared according to the method presentedfor the synthesis of compound 355, starting with 398B. ES/MS (m/z) 695.2(M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 13.11-12.65 (s, 1H), 8.87 (d, J=8.1Hz, 1H), 8.85-8.83 (m, 1H), 8.73-8.65 (m, 1H), 8.61 (ddd, J=4.4, 2.3,1.2 Hz, 1H), 8.08 (dd, J=8.8, 1.3 Hz, 1H), 7.87 (dd, J=8.6, 4.4 Hz, 1H),7.75 (d, J=7.6 Hz, 1H), 7.71-7.63 (m, 2H), 6.69 (d, J=13.4 Hz, 1H), 6.65(s, 1H), 4.88-4.80 (m, 1H), 4.77 (d, J=11.5 Hz, 1H), 4.14 (d, J=12.6 Hz,1H), 3.94 (dd, J=11.4, 3.6 Hz, 1H), 3.81-3.68 (m, 2H), 3.57 (d, J=2.5Hz, 3H), 3.55-3.42 (m, 2H), 3.35 (d, J=12.4 Hz, 1H), 3.25 (t, J=12.1 Hz,1H), 2.03 (d, J=2.5 Hz, 3H).

Example 399

(S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,2-d]pyrimidin-3(2H)-yl)quinolin-5-yl)propanoicacid (399): The title compound was prepared according to the methodpresented for the synthesis of compound 356, starting with 398. ES/MS(m/z) 681.2 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 9.00 (d, J=7.8 Hz, 1H),8.88-8.81 (m, 1H), 8.67 (d, J=8.6 Hz, 1H), 8.61 (ddd, J=4.4, 2.1, 1.3Hz, 1H), 8.08 (dd, J=8.8, 1.3 Hz, 1H), 7.87 (dd, J=8.6, 4.4 Hz, 1H),7.76 (d, J=7.5 Hz, 1H), 7.67 (dt, J=7.8, 3.3 Hz, 2H), 6.70 (dd, J=13.0,2.3 Hz, 1H), 6.66 (d, J=2.4 Hz, 1H), 4.86 (d, J=4.3 Hz, 1H), 4.83 (m,1H), 4.14 (d, J=12.6 Hz, 1H), 3.95 (dd, J=11.3, 3.7 Hz, 1H), 3.78-3.70(m, 2H), 3.69 (d, J=3.6 Hz, 3H), 3.57 (d, J=2.4 Hz, 3H), 3.53 (d, J=3.7Hz, 1H), 3.51 (d, J=9.9 Hz, 1H), 3.36 (d, J=12.3 Hz, 1H), 3.25 (t,J=12.2 Hz, 1H), 2.05 (s, 3H).

Example 400

Synthesis of methyl(S)-4-(3-(5-(3-methoxy-3-oxo-2-(tritylamino)propyl)quinolin-8-yl)ureido)nicotinate(400A): Phosgene (15% solution in toluene, 2.18 mL, 3.06 mmol, 2 eq.),was added to a flame-dried vial containing a solution of methyl4-aminonicotinate (0.466 g, 3.06 mmol, 2 eq.), DIEA (0.8 mL, 4.59 mmol,3 eq.), and DCM (2 mL). The combined reagents were stirred at roomtemperature for 1 h, then 355B (0.746 g, 1.53 mmol, 1 eq.) was added.The reaction was stirred at room temperature for 1 h. The reactionmixture was then adsorbed onto silica gel and purified by columnchromatography using methanol in DCM as the eluent (0-5%). Appropriatefractions were then combined and concentrated under vacuum to afford thetitle compound.

Synthesis of methyl(S)-3-(8-(1-methyl-2,4-dioxo-1,4-dihydropyrido[4,3-d]pyrimidin-3(2H)-yl)quinolin-5-yl)-2-(tritylamino)propanoate(400B): The title compound was prepared according to the methodpresented for the synthesis of compound 355E, starting with 400A.

Methyl (S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(1-methyl-2,4-dioxo-1,4-dihydropyrido[4,3-d]pyrimidin-3(2H)-yl)quinolin-5-yl)propanoate(400): The title compound was prepared according to the method presentedfor the synthesis of compound 355, starting with 400B. ES/MS (m/z) 695.2(M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 9.10 (d, J=3.0 Hz, 1H), 9.00 (d,J=7.7 Hz, 1H), 8.88-8.80 (m, 2H), 8.66 (dd, J=8.7, 1.6 Hz, 1H), 7.76 (d,J=7.6 Hz, 1H), 7.67 (td, J=5.8, 5.3, 2.6 Hz, 2H), 7.61 (d, J=6.1 Hz,1H), 6.74-6.59 (m, 2H), 4.88-4.78 (m, 2H), 4.15 (d, J=12.7 Hz, 1H),3.97-3.87 (m, 1H), 3.77-3.64 (m, 5H), 3.57 (d, J=2.2 Hz, 5H), 3.36 (d,J=12.3 Hz, 1H), 3.25 (t, J=12.1 Hz, 1H), 2.05 (s, 3H).

Example 401

(S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,2-d]pyrimidin-3(2H)-yl)quinolin-5-yl)propanoicacid (401): The title compound was prepared according to the methodpresented for the synthesis of compound 356, starting with 400. ES/MS(m/z) 681.2 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 9.10 (d, J=3.6 Hz, 1H),8.95-8.76 (m, 3H), 8.68 (d, J=8.7 Hz, 1H), 7.76 (d, J=7.5 Hz, 1H),7.74-7.56 (m, 3H), 6.74-6.56 (m, 2H), 4.90-4.72 (m, 2H), 4.14 (d, J=12.6Hz, 1H), 3.94 (dd, J=11.4, 3.6 Hz, 1H), 3.75 (t, J=13.4 Hz, 2H), 3.57(d, J=2.4 Hz, 3H), 3.55-3.48 (m, 1H), 3.47 (s, 1H), 3.35 (d, J=12.6 Hz,1H), 3.25 (t, J=12.4 Hz, 1H), 2.03 (s, 3H).

Example 402

Synthesis of methyl(S)-2-(3-(5-(3-methoxy-3-oxo-2-(tritylamino)propyl)quinolin-8-yl)ureido)nicotinate(402A): To a solution of 355B (60.0 mg, 0.123 mmol) in DCM (0.62 mL, 0.2mmol) in a flamed-dried vial was added methyl 2-aminonicotinate (37.0mg, 0.246 mmol) and DIEA (48.0 mg, 0.369 mmol) and the mixture wasstirred for 2 min at rt. A solution of phosgene in toluene (162 mg,0.246 mmol) was added drop-wise and reaction mixture was stirred for anadditional hour at rt. Upon completion, the solvent was removed underreduced pressure and the product was purified using flash chromatographyeluting with MeOH in dichloromethane 0-20% to afford the title compound.

Synthesis of methyl(S)-3-(8-(1-methyl-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidin-3(2H)-yl)quinolin-5-yl)-2-(tritylamino)propanoate(400B): The title compound was prepared according to the methodpresented for the synthesis of compound 355E, starting with 402A.

Methyl (S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(1-methyl-2,4-dioxo-1,4-dihydropyrido[2,3-d]pyrimidin-3(2H)-yl)quinolin-5-yl)propanoate(402C): The title compound was prepared according to the methodpresented for the synthesis of compound 355, starting with 402B.

(S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,2-d]pyrimidin-3(2H)-yl)quinolin-5-yl)propanoicacid (402): The title compound was prepared according to the methodpresented for the synthesis of compound 356, starting with 402C. ES/MS(m/z) 681.2 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 8.86 (d, J=8.0 Hz, 3H),8.68 (d, J=8.4 Hz, 1H), 8.42 (d, J=9.3 Hz, 1H), 7.76 (d, J=7.5 Hz, 1H),7.70-7.63 (m, 2H), 7.45-7.39 (m, 1H), 6.73-6.63 (m, 2H), 4.87-4.72 (m,3H), 4.14 (d, J=12.6 Hz, 1H), 3.99-3.91 (m, 2H), 3.74 (s, 2H), 3.63 (s,3H), 3.58-3.51 (m, 1H), 3.50-3.42 (m, 1H), 3.38-3.31 (m, 1H), 3.28-3.21(m, 1H), 2.03 (s, 3H).

Example 403

Synthesis of methyl(S)-3-(3-(5-(3-methoxy-3-oxo-2-(tritylamino)propyl)quinolin-8-yl)ureido)pyrazine-2-carboxylate(403A): To a vial equipped with a stir bar was added3-(methoxycarbonyl)pyrazine-2-carboxylic acid (0.18 g, 1.01 mmol, 1.5eq.), triethylamine (0.28 mL, 2.02 mmol, 3.0 eq.), DPPA (0.17 mL, 0.81mmol, 1.2 eq.), 355B (0.33 g, 0.67 mmol, 1.0 eq.), and toluene (3.36 mL.0.2 M). The reaction was then heated to 100° C. for 30 min. The reactionwas quenched with water (10 mL) and extracted with EtOAc (25 mL, 3×).The combined organic phases were washed with sat. sodium bicarbonate,brine, and dried over anhydrous Na₂SO₄. Organic phases were concentratedand the product was purified by column chromatography using a stepwiseelution gradient of 0-100% EtOAc in hexanes.

Synthesis of methyl(S)-3-(8-(1-methyl-2,4-dioxo-1,4-dihydropteridin-3(2H)-yl)quinolin-5-yl)-2-(tritylamino)propanoate(403B): The title compound was prepared according to the methodpresented for the synthesis of compound 355E, starting with 403A.

Methyl (S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(1-methyl-2,4-dioxo-1,4-dihydropteridin-3(2H)-yl)quinolin-5-yl)propanoate(403): The title compound was prepared according to the method presentedfor the synthesis of compound 355, starting with 403B. ES/MS (m/z) 696.1(M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 9.00 (d, J=7.8 Hz, 1H), 8.92-8.86(m, 2H), 8.73-8.68 (m, 2H), 7.78 (d, J=7.5 Hz, 1H), 7.73-7.67 (m, 2H),6.74-6.64 (m, 2H), 4.90-4.79 (m, 2H), 4.15 (d, J=12.6 Hz, 1H), 3.95 (dd,J=11.5, 3.5 Hz, 1H), 3.80-3.65 (m, 5H), 3.61 (s, 3H), 3.55 (t, J=13.9,7.6, 2.5 Hz, 2H), 3.36 (d, J=11.8 Hz, 1H), 3.25 (t, 1H), 2.05 (s, 3H).

Example 404

(S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(1-methyl-2,4-dioxo-1,4-dihydropteridin-3(2H)-yl)quinolin-5-yl)propanoicacid (404): The title compound was prepared according to the methodpresented for the synthesis of compound 356, starting with 403. ES/MS(m/z) 682.7 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 8.93-8.83 (m, 3H),8.75-8.67 (m, 2H), 7.77 (d, J=7.5 Hz, 1H), 7.74-7.66 (m, 2H), 6.73-6.62(m, 2H), 4.89-4.75 (m, 2H), 4.14 (d, J=12.6 Hz, 1H), 3.94 (dd, J=11.7,3.5 Hz, 1H), 3.81-3.69 (m, 2H), 3.61 (s, 3H), 3.59-3.43 (m, 2H), 3.35(d, J=12.2 Hz, 1H), 3.25 (t, 1H), 2.03 (d, J=2.4 Hz, 3H).

Example 405

Synthesis of methyl(S)-4-(3-(5-(3-methoxy-3-oxo-2-(tritylamino)propyl)quinolin-8-yl)ureido)pyrimidine-5-carboxylate(405A): DIEA (0.5 mL, 3.1 mmol, 3 eq.) and triphosgene (212 mg, 0.72mmol, 0.7 eq.) were added to a solution of methyl4-aminopyrimidine-5-carboxylate (314 mg, 2.0 mmol, 2 eq.) in DCM (0.2M). The solution was stirred at ambient temperature for 1 hour. 355B(500 mg, 1 mmol, 1 eq.) was then added to the solution and stirred foran hour at ambient temperature. The reaction mixture was concentrateddirectly onto silica gel and chromatographed eluting with 0-100% ethylacetate in hexanes; the product eluted at 75%.

Synthesis of methyl(S)-3-(8-(1-methyl-2,4-dioxo-1,4-dihydropyrimido[4,5-d]pyrimidin-3(2H)-yl)quinolin-5-yl)-2-(tritylamino)propanoate(405B): The title compound was prepared according to the methodpresented for the synthesis of compound 355E, starting with 405A.

Methyl(S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(1-methyl-2,4-dioxo-1,4-dihydropyrimido[4,5-d]pyrimidin-3(2H)-yl)quinolin-5-yl)propanoate(405): The title compound was prepared according to the method presentedfor the synthesis of compound 355, starting with 405B. ES/MS (m/z) 696.8(M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 9.32 (s, 1H), 9.26-9.18 (m, 1H),8.99 (d, J=7.8 Hz, 1H), 8.91-8.84 (m, 1H), 8.67 (d, J=8.7 Hz, 1H),7.82-7.73 (m, 1H), 7.72-7.63 (m, 2H), 6.76-6.64 (m, 2H), 4.88-4.80 (m,2H), 4.15 (d, J=12.6 Hz, 1H), 3.98-3.91 (m, 1H), 3.78-3.70 (m, 2H), 3.68(s, 3H), 3.61 (s, 3H), 3.58-3.51 (m, 2H), 3.42-3.32 (m, 1H), 3.30-3.18(m, 1H), 2.04 (s, 3H).

Example 406

(S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(1-methyl-2,4-dioxo-1,4-dihydropyrimido[4,5-d]pyrimidin-3(2H)-yl)quinolin-5-yl)propanoicacid (406): The title compound was prepared according to the methodpresented for the synthesis of compound 356, starting with 405. ES/MS(m/z) 682.2 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 9.32 (s, 1H), 9.25-9.18(m, 1H), 8.91-8.82 (m, 2H), 8.69 (d, J=8.6 Hz, 1H), 7.80-7.73 (m, 1H),7.73-7.64 (m, 2H), 6.75-6.60 (m, 2H), 4.90-4.74 (m, 2H), 4.14 (d, J=12.6Hz, 1H), 3.95 (d, J=10.8 Hz, 1H), 3.81-3.68 (m, 2H), 3.60 (s, 3H),3.58-3.40 (m, 2H), 3.39-3.31 (m, 1H), 3.31-3.18 (m, 1H), 2.02 (s, 3H).

Examples 407 and 408

Preparation of(S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)quinolin-5-yl)propanoicacid (407): 356 was separated into its 2 atropisomeric enantiomers bysupercritical fluid chromatography using 30% EtOH co-solvent, at a flowrate of 3 mL/min, using an AD-H 5 μm 4.6×100 mm column. The titlecompound was identified as the second eluting peak. ES/MS (m/z) 681.2(M+H)+. 1H NMR (400 MHz, Chloroform-d) δ 8.84-8.72 (m, 2H), 8.66 (d,J=8.6 Hz, 1H), 8.55 (s, 1H), 8.00 (s, 1H), 7.58 (s, 2H), 7.44 (dd,J=8.6, 4.2 Hz, 1H), 6.66 (d, J=6.5 Hz, 1H), 6.46 (s, 1H), 6.37 (d,J=13.6 Hz, 1H), 5.08 (d, J=7.0 Hz, 1H), 4.29 (d, J=12.4 Hz, 1H), 4.11(dd, J=8.2, 3.8 Hz, 1H), 4.04 (dd, J=11.3, 3.5 Hz, 1H), 3.84-3.70 (m,3H), 3.68 (s, 3H), 3.65-3.56 (m, 1H), 3.50 (t, J=12.0 Hz, 1H), 3.26 (d,J=12.2 Hz, 1H), 2.38 (s, 3H).

Preparation(S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)quinolin-5-yl)propanoicacid (408): 356 was separated into its 2 atropisomeric enantiomers bysupercritical fluid chromatography using 30% EtOH co-solvent, at a flowrate of 3 mL/min, using an AD-H 5 μm 4.6×100 mm column. The titlecompound was identified as the first eluting peak. ES/MS (m/z) 681.2(M+H)+. 1H NMR (400 MHz, Chloroform-d) δ 8.83-8.72 (m, 2H), 8.64 (d,J=8.6 Hz, 1H), 8.56 (d, J=5.0 Hz, 1H), 8.03 (d, J=5.0 Hz, 1H), 7.59 (q,J=7.6 Hz, 2H), 7.46 (dd, J=8.6, 4.2 Hz, 1H), 6.63 (d, J=6.1 Hz, 1H),6.47 (s, 1H), 6.38 (dd, J=13.4, 2.4 Hz, 1H), 5.13-5.02 (m, 1H), 4.30 (d,J=12.4 Hz, 1H), 4.12 (dd, J=8.0, 3.8 Hz, 1H), 4.04 (dd, J=11.2, 3.5 Hz,1H), 3.86-3.78 (m, 1H), 3.72 (t, J=5.6 Hz, 2H), 3.69 (s, 3H), 3.65-3.59(m, 1H), 3.51 (t, J=11.7 Hz, 1H), 3.27 (d, J=12.3 Hz, 1H), 2.39 (s, 3H).

Examples 487 and 488

Preparation ethyl(S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)quinolin-5-yl)propanoate(487): 360 was separated into its 2 atropisomeric enantiomers bysupercritical fluid chromatography using 30% EtOH co-solvent, at a flowrate of 3 mL/min, using an AD-H 5 μm 4.6×100 mm column. The titlecompound was identified as the first eluting peak. ES/MS (m/z) 709.2(M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 9.04 (s, 1H), 8.99 (d, J=7.7 Hz,1H), 8.84 (dd, J=4.1, 1.5 Hz, 1H), 8.64 (dd, J=8.6, 1.6 Hz, 1H), 8.60(d, J=4.9 Hz, 1H), 7.91 (dd, J=4.9, 0.7 Hz, 1H), 7.75 (d, J=7.6 Hz, 1H),7.69-7.63 (m, 2H), 6.76-6.63 (m, 2H), 4.90-4.74 (m, 2H), 4.19-4.06 (m,3H), 3.95 (dd, J=11.4, 3.6 Hz, 1H), 3.78-3.67 (m, 2H), 3.65 (s, 3H),3.61-3.46 (m, 2H), 3.37 (s, 1H), 3.31-3.18 (m, 1H), 2.07 (s, 3H), 1.16(t, J=7.1 Hz, 3H).

Preparation ethyl(S)-2-(2-fluoro-6-methyl-4-((R)-3-(trifluoromethyl)morpholino)benzamido)-3-(8-(1-methyl-2,4-dioxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)quinolin-5-yl)propanoate(488): 360 was separated into its 2 atropisomeric enantiomers bySimulated moving bed (SMB) chromatography using EA/heptanes (80/20),using a ChiralPak IC column. The title compound was identified as thesecond eluting peak. ES/MS (m/z) 709.2 (M+H)+. 1H NMR (400 MHz, DMSO-d6)δ 9.04 (s, 1H), 8.99 (d, J=7.7 Hz, 1H), 8.84 (dd, J=4.2, 1.5 Hz, 1H),8.64 (dd, J=8.7, 1.6 Hz, 1H), 8.60 (d, J=5.0 Hz, 1H), 7.91 (d, J=4.9 Hz,1H), 7.75 (d, J=7.5 Hz, 1H), 7.69-7.63 (m, 2H), 6.75-6.62 (m, 2H),4.91-4.75 (m, 2H), 4.20-4.07 (m, 3H), 3.95 (dd, J=11.4, 3.6 Hz, 1H),3.78-3.67 (m, 2H), 3.66 (s, 3H), 3.60-3.47 (m, 2H), 3.36 (d, J=12.3 Hz,1H), 3.25 (t, J=12.3 Hz, 1H), 2.07 (s, 3H), 1.16 (t, J=7.1 Hz, 3H).

α4β7 Integrin Cell Capture Assay

The potency of inhibitors in preventing α4β7 integrin interaction withMadCAM-1 was measured by monitoring the capture of α4β7 integrinexpressing cells on a recombinant MadCAM-1 extracellular domain-coatedplate. 384-Well plates (Corning 3702) were coated with MadCAM-1extracellular domain by dispensing 20 μL of MAdCAM-1 at 1.0 μg/mL perwell and incubating overnight at 4° C. The plates were then washed withPBS and blocked with 3% BSA for 2 hours before being washed again.

RPM18866 cells were spun down and re-suspended in assay medium(DMEM+0.5% FBS+0.5 mM MnCl₂) at a density of 0.5×10⁶ cells/mL. The cellswere then dispensed (60 μL/well) to a 384-well plate (Greiner 781280)that was previously spotted with 60 nL of test compound per well. Theplates were incubated at 37° C. for 1 hour. 50 μL of cells weretransferred to the blocked, MadCAM-1-coated plates and incubated for 30minutes at 37° C. 10 μL of 12% glutaraldehyde containing Hoechst 33342(0.06 mg/mL) was added to the cells (2% glutaraldehyde and 0.01 mg/mLfinal concentrations). The plates were incubated for 90 minutes at roomtemperature. The plates were then washed 3 times with 70 μL of PBS perwell and imaged on a Cellomics ArrayScan instrument. The cells that werebound to the plate were counted and plotted against the compoundconcentration to determine the EC₅₀ of the test compounds. Results werepresented in Tables 1 and 2.

TABLE 1 Example # α4β7 EC₅₀ (nM) 1 21.2 2 31.1 3 63.8 4 6.7 5 17.4 6 4.57 1.9 8 41.4 9 25.1 10 21.2 11 22.9 12 7.0 13 8.5 14 3.7 15 9.3 16 67.417 36.7 18 9.0 19 50.0 20 185.8 21 96.6 22 48.5 23 46.7 24 56.7 25 3.326 32.8 27 12.8 28 33.5 29 68.7 30 16.9 31 19.3 32 75.9 33 60.5 34 39.535 6.2 36 21.0 37 69.6 38 29.7 39 81.6 40 8.6 41 7.7 42 13.4 43 4.6 4410.9 45 3.4 46 20.0 47 2.4 48 52.1 49 33.7 50 0.4 51 2.9 52 91.5 53 3.054 37.4 55 27.4 56 9.1 57 30.0 58 2.0 59 3.2 60 3.0 61 4.2 62 1.8 6330.5 64 0.8 65 8.4 66 18.9 67 1.6 68 14.0 69 28.9 70 10.7 71 9.5 72 5.573 2.5 74 13.6 75 80.4 76 78.4 77 90.7 78 134.3 79 26.1 80 18.1 81 6.082 4.7 83 32.9 84 11.7 85 25.4 86 8.3 87 15.0 88 8.2 89 14.4 90 11.3 910.3 92 2.0 93 0.4 94 0.5 95 0.3 96 0.2 97 3.2 98 1.4 99 11.2 100 0.7 1014.1 102 0.3 103 0.7 104 0.5 105 4.1 106 0.3 107 0.2 108 1.0 109 0.3 1100.3 111 0.1 112 0.4 113 1.2 114 0.6 115 0.6 116 1.2 117 0.7 118 1.5 11920.5 120 1.3 121 1.7 122 0.2 123 0.9 124 0.6 125 1.0 126 0.6 127 9.3 1280.3 129 0.7 130 0.5 131 0.8 132 1.3 133 3.2 134 4.2 135 0.4 136 0.2 1370.4 138 0.8 139 11.7 140 0.5 141 0.1 142 0.2 143 0.3 144 0.2 145 3.1 1460.6 147 1.9 148 60.6

Examples 149-354 in Table 2 were prepared by processes described herein.

TABLE 2 α4β7 Ex- M/Z EC₅₀ ample Structure 1H-NMR [M + H]+ (nM) 149

1H NMR (400 MHz, DMSO-d6) δ 9.26 (dd, J = 8.0, 3.2 Hz, 1H), 8.81 (dd, J= 4.2, 1.5 Hz, 1H), 8.62 (d, J = 8.9 Hz, 1H), 7.66-7.54 (m, 3H),7.54-7.41 (m, 2H), 7.32-7.23 (m, 1H), 7.14-7.04 (m, 3H), 6.89 (d, J =1.6 Hz, 1H), 4.78 (d, J = 2.4 Hz, 1H), 3.85-3.67 (m, 1H), 3.41 (ddd, J =21.8, 14.7, 10.2 Hz, 1H), 1.21 (s, 1H). 550.9 50.3 150

1H NMR (400 MHz, DMSO-d6) δ 9.24 (d, J = 8.2 Hz, 1H), 8.86 (dd, J = 4.2,1.6 Hz, 1H), 8.67 (dd, J = 8.7, 1.7 Hz, 1H), 8.17 (d, J = 1.6 Hz, 1H),7.92 (dd, J = 7.9, 1.7 Hz, 1H), 7.70-7.61 (m, 3H), 7.58 (d, J = 7.9 Hz,1H), 7.22 (d, J = 9.3 Hz, 2H), 6.49 (tt, J = 3.1, 1.5 Hz, 1H), 4.78(ddd, J = 10.2, 8.1, 4.4 Hz, 1H), 4.22 (p, J = 3.4, 2.9 Hz, 2H), 3.79(t, J = 5.4 Hz, 2H), 3.42 (s, 1H), 2.46-2.34 (m, 2H). 573.8 43.6 151

1H NMR (400 MHz, DMSO-d6) δ 8.96 (d, J = 8.0 Hz, 1H), 8.88 (s, 1H), 8.74(s, 1H), 7.66 (d, J = 29.5 Hz, 3H), 6.77 (d, J = 11.8 Hz, 2H), 4.98-4.84(m, 1H), 4.68 (s, 1H), 4.16 (d, J = 12.7 Hz, 1H), 3.99- 3.90 (m, 1H),3.72 (s, 3H), 3.52 (d, J = 1.6 Hz, 3H), 3.49-3.37 (m, 2H), 3.23 (t, J =12.5 Hz, 1H), 2.41 (s, 3H), 2.33 (d, J = 2.0 Hz, 3H). 646.2 0.2 152

1H NMR (400 MHz, DMSO-d6) δ 8.83 (dd, J = 4.2, 1.6 Hz, 1H), 8.77 (d, J =8.0 Hz, 1H), 8.64 (dd, J = 8.7, 1.7 Hz, 1H), 8.15 (d, J = 1.6 Hz, 1H),7.89 (dd, J = 7.9, 1.6 Hz, 1H), 7.70-7.58 (m, 3H), 7.57 (d, J = 7.9 Hz,1H), 7.01 (s, 1H), 5.94 (d, J = 11.0 Hz, 2H), 4.67 (s, 1H), 4.54 (d, J =6.1 Hz, 2H), 4.47 (dd, J = 6.0, 1.2 Hz, 2H), 3.72 (s, 1H), 3.41 (s, 1H),1.51 (s, 3H). 578.1 51.7 153

1H NMR (400 MHz, DMSO-d6) δ 9.25 (d, J = 8.1 Hz, 1H), 8.90 (d, J = 4.4Hz, 1H), 8.81 (d, J = 8.4 Hz, 1H), 7.99 (s, 1H), 7.82-7.57 (m, 5H),7.46-7.11 (m, 3H), 6.93 (dd, J = 17.5, 9.3 Hz, 3H), 4.78-4.70 (m, 1H),3.77 (dd, J = 14.5, 4.5 Hz, 1H), 3.68 (s, 3H), 3.43 (dd, J = 14.5, 9.9Hz, 1H). 643.1 0.2 154

1H NMR (400 MHz, DMSO-d6) δ 9.38 (d, J = 8.2 Hz, 1H), 9.01 (d, J = 8.5Hz, 1H), 8.84 (dd, J = 4.1, 1.6 Hz, 1H), 8.64 (dd, J = 8.7, 1.6 Hz, 1H),8.16 (dd, J = 1.6, 0.4 Hz, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.68- 7.53 (m,7H), 1.34 (d, J = 7.1 Hz 4H). 630.8 44.6 155

1H NMR (400 MHz, DMSO-d6) δ 8.86-8.74 (m, 2H), 8.64 (s, 1H), 7.62 (dd, J= 8.7, 4.4 Hz, 1H), 7.55 (dd, J = 7.4, 5.1 Hz, 1H), 7.42 (dd, J = 7.3,4.2 Hz, 1H), 6.92 (dd, J = 9.5, 5.5 Hz, 1H), 6.54 (s, 1H), 6.40 (dd, J =11.4, 4.1 Hz, 2H), 4.71- 4.60 (m, 1H), 3.91 (q, J = 8.0 Hz, 1H),3.75-3.60 (m, 1H), 3.47 (d, J = 2.4 Hz, 3H), 3.44-3.30 (m, 1H), 2.51 (s,3H), 1.03 (ddd, J = 13.0, 8.8, 4.9 Hz, 1H), 0.68-0.56 (m, 1H), 0.54-0.41(m, 2H), 0.30 (dd, J = 9.6, 4.8 Hz, 1H). 682.6 0.3 156

1H NMR (400 MHz, DMSO-d6) δ 8.98-8.88 (m, 2H), 8.81 (d, J = 8.1 Hz, 1H),7.96 (d, J = 8.0 Hz, 1H), 7.88-7.66 (m, 4H), 7.64 (d, J = 8.7 Hz, 1H),7.36 (t, J = 7.6 Hz, 1H), 6.84 (d, J = 9.1 Hz, 1H), 6.48-6.36 (m, 2H),4.80-4.69 (m, 1H), 4.58-4.43 (m, 1H), 3.87 (dd, J = 14.1, 4.0 Hz, 1H),3.76- 3.52 (m, 4H), 3.29 (d, J = 2.5 Hz, 3H), 1.28 (d, J = 6.6 Hz, 3H).655.3 0.3 157

1H NMR (400 MHz, DMSO-d6) δ 9.29 (d, J = 8.4 Hz, 1H), 8.85 (dd, J = 4.1,1.5 Hz, 1H), 8.70 (d, J = 8.7 Hz, 1H), 8.20 (d, J = 8.0 Hz, 1H),7.83-7.72 (m, 3H), 7.69 (dd, J = 8.6, 4.2 Hz, 1H), 7.54 (ddd, J = 8.3,6.5, 1.9 Hz, 1H), 7.46-7.35 (m, 3H), 7.27 (dd, J = 15.0, 7.3 Hz, 1H),6.70 (t, J = 7.6 Hz, 1H), 4.85 (s, 1H), 3.42 (dd, J = 14.5, 10.3 Hz,1H). 532.0 44.0 158

1H NMR (400 MHz, DMSO-d6) δ 12.85 (s, 1H), 8.97 (dd, J = 8.0, 4.9 Hz,1H), 8.86 (d, J = 4.3 Hz, 1H), 8.79-8.70 (m, 1H), 7.69 (td, J = 7.8, 4.4Hz, 1H), 7.61 (t, J = 7.7 Hz, 1H), 7.49 (dd, J = 7.4, 3.8 Hz, 1H), 6.75(dd, J = 11.7, 3.7 Hz, 2H), 6.34 (s, 1H), 4.90 (dt, J = 11.7, 5.8 Hz,1H), 4.77-4.67 (m, 1H), 4.16 (d, J = 12.7 Hz, 2H), 3.95 (dd, J = 11.5,3.7 Hz, 1H), 3.81-3.67 (m, 1H), 3.66 (s, 3H), 3.61-3.37 (m, 3H), 3.24(t, J = 12.2 Hz, 1H), 2.17 (td, J = 8.4, 4.2 Hz, 1H), 1.10 (d, J = 8.6Hz, 2H), 0.94 (dq, J = 17.4, 7.0, 4.0 Hz, 2H). 725.2 0.3 159

1H NMR (400 MHz, DMSO-d6) δ 8.97 (d, J = 7.9 Hz, 1H), 8.86 (d, J = 2.7Hz, 1H), 8.38 (dt, J = 10.6, 2.6 Hz, 1H), 7.60 (t, J = 8.2 Hz, 1H), 7.41(dd, J = 7.3, 5.2 Hz, 1H), 6.75 (d, J = 11.7 Hz, 2H), 6.54 (s, 1H), 4.91(dd, J = 9.0, 3.5 Hz, 1H), 4.70 (tt, J = 7.9, 3.6 Hz, 1H), 4.15 (d, J =12.7 Hz, 1H), 3.95 (dd, J = 11.4, 3.8 Hz, 1H), 3.73 (d, J = 12.9 Hz,1H), 3.65 (dd, J = 14.1, 4.4 Hz, 1H), 3.62-3.51 (m, 1H), 3.48 (d, J =1.5 Hz, 3H), 3.47-3.38 (m, 2H), 3.23 (t, J = 12.4 Hz, 1H), 2.52 (s, 3H).717.0 0.3 160

1H NMR (400 MHz, DMSO-d6) δ 8.96-8.80 (m, 2H), 8.75-8.64 (m, 1H),7.73-7.61 (m, 2H), 7.46 (t, J = 7.8 Hz, 1H), 6.84 (d, J = 8.7 Hz, 1H),6.79 (d, J = 9.3 Hz, 1H), 6.56 (d, J = 4.5 Hz, 1H), 4.91- 4.69 (m, 2H),4.13 (d, J = 12.7 Hz, 1H), 3.93 (d, J = 11.3 Hz, 1H), 3.82-3.64 (m, 2H),3.58-3.41 (m, 4H), 3.36-3.20(m, 3H), 2.54 (s, 3H), 2.02 (s, 3H). 711.20.3 161

1H NMR (400 MHz, DMSO-d6) δ 8.99-8.93 (m, 2H), 8.85 (d, J = 8.7 Hz, 1H),7.80-7.71 (m, 2H), 7.65 (d, J = 7.4 Hz, 1H), 7.57 (s, 1H), 6.76 (d, J =11.7 Hz, 2H), 4.96-4.85 (m, 1H), 4.74-4.66 (m, 1H), 4.16 (d, J = 12.7Hz, 1H), 3.95 (dd, J = 11.5, 3.7 Hz, 1H), 3.79-3.69 (m, 2H), 3.60-3.51(m, 4H), 3.50-3.37 (m, 2H), 3.23 (t, 1H), 2.57 (s, 3H). 665.2 0.3 162

1H NMR (400 MHz, DMSO-d6) δ 9.35 (d, J = 8.2 Hz, 1H), 8.97 (d, J = 7.9Hz, 1H), 8.84 (dd, J = 4.1, 1.6 Hz, 1H), 8.68-8.60 (m, 1H), 8.16 (d, J =1.6 Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.60 (td, J = 15.7, 15.0, 8.2 Hz,6H), 7.38-7.28 (m, 4H), 7.21 (t, J = 7.1 Hz, 1H), 5.11 (t, J = 7.3 Hz,1H), 4.79 (d, J = 12.5 Hz, 1H), 3.41 (s, 1H), 2.65 (s, 1H), 2.31 (s,1H), 1.45 (d, J = 7.0 Hz, 3H). 639.2 53.5 163

1H NMR (400 MHz, DMSO-d6) δ 13.00 (s, 1H), 8.86 (d, J = 3.8 Hz, 1H),8.81 (dd, J = 7.9, 5.5 Hz, 1H), 8.73 (t, J = 7.5 Hz, 1H), 7.69 (dt, J =8.8, 5.1 Hz, 1H), 7.60 (t, J = 6.6 Hz, 1H), 7.48 (dd, J = 7.4, 3.2 Hz,1H), 6.76 (dd, J = 9.5, 4.7 Hz, 1H), 6.44 (dd, J = 11.4, 3.6 Hz, 2H),6.34 (s, 1H), 4.70 (tt, J = 8.2, 4.1 Hz, 1H), 4.35-4.26 (m, 1H), 3.79-3.63 (m, 4H), 3.52-3.35 (m, 1H), 2.17 (ddd, J = 13.8, 8.4, 5.5 Hz, 1H),1.85-1.70 (m, 1H), 1.61- 1.45 (m, 1H), 1.16-1.04 (m, 2H), 1.02-0.87 (m,2H), 0.93 (t, J = 7.3 Hz, 3H). 697.2 0.4 164

1H NMR (400 MHz, DMSO-d6) δ 8.86-8.79 (m, 2H), 8.63 (dd, J = 8.6, 1.7Hz, 1H), 8.15 (dd, J = 1.7, 0.4 Hz, 1H), 7.90 (dd, J = 7.9, 1.6 Hz, 1H),7.68-7.51 (m, 4H), 7.16 (s, 1H), 6.09 (d, J = 11.1 Hz, 2H), 4.68 (s,1H), 3.72 (s, 1H), 3.41 (s, 1H), 2.53 (dd, J = 13.0, 6.5 Hz, 2H),2.36-2.26 (m, 2H), 1.95 (dd, J = 15.1, 6.8 Hz, 2H). 629.2 88.6 165

1H NMR (400 MHz, DMSO-d6) δ 8.98-8.88 (m, 2H), 8.84 (t, J = 8.0 Hz, 1H),8.13 (s, 1H), 7.81- 7.71 (m, 1H), 7.67 (dd, J = 15.1, 7.4 Hz, 1H), 7.57(dd, J = 10.9, 7.3 Hz, 1H), 6.74 (dd, J = 11.7, 2.5 Hz, 2H), 4.95-4.84(m, 1H), 4.80- 4.68 (m, 1H), 4.16 (d, J = 12.7 Hz, 1H), 3.95 (dd, J =11.5, 3.8 Hz, 1H), 3.77-3.65 (m, 1H), 3.60- 3.49 (m, 2H), 3.48-3.33 (m,5H), 3.29-3.17 (m, 1H), 1.82 (d, J = 10.8 Hz, 3H). 665.2 0.4 166

1H NMR (400 MHz, DMSO-d6) δ 9.16-9.01 (m, 1H), 8.97 (d, J = 4.7 Hz, 1H),8.84 (d, J = 7.9 Hz, 1H), 7.98-7.82 (m, 1H), 7.76- 7.63 (m, 2H), 6.96(d, J = 9.5 Hz, 1H), 6.50-6.38 (m, 3H), 4.74- 4.64 (m, 1H), 3.93 (q, J =8.0 Hz, 1H), 3.84-3.69 (m, 1H), 3.67 (d, J = 4.4 Hz, 3H), 3.55-3.41 (m,4H), 2.51 (s, 3H), 1.11-1.00 (m, 1H), 0.67-0.59 (m, 1H), 0.56- 0.44 (m,2H), 0.35-0.27 (m, 1H). 645.2 0.4 167

1H NMR (400 MHz, DMSO-d6) δ 12.93 (s, 1H), 8.92-8.85 (m, 1H), 8.82-8.73(m, 2H), 7.78-7.68 (m, 1H), 7.64 (dd, J = 16.6, 7.4 Hz, 1H), 7.52 (dd, J= 9.7, 7.3 Hz, 1H), 6.77 (d, J = 9.3 Hz, 1H), 6.49 (d, J = 3.0 Hz, 1H),6.43 (dd, J = 11.4, 4.7 Hz, 2H), 6.12 (td, J = 54.6, 12.8 Hz, 1H),4.78-4.65 (m, 1H), 4.35-4.25 (m, 1H), 3.85- 3.63 (m, 1H), 3.51-3.48 (m,3H), 3.54-3.32 (m, 1H), 2.53 (s, 3H), 1.84-1.70 (m, 1H), 1.61- 1.44 (m,1H), 0.92 (t, J = 7.3 Hz, 3H). 653.2 0.4 168

1H NMR (400 MHz, DMSO-d6) δ 8.75 (s, 1H), 8.61 (s, 1H), 7.58 (dd, J =22.2, 8.5 Hz, 2H), 7.45 (d, J = 7.0 Hz, 1H), 7.36 (dd, J = 9.4, 2.7 Hz,1H), 7.03 (s, 1H), 6.75 (d, J = 9.4 Hz, 1H), 6.53 (s, 1H), 6.45 (d, J =11.6 Hz, 2H), 4.31 (s, 1H), 3.73 (d, J = 13.2 Hz, 1H), 3.66 (s, 3H),2.97 (s, 5H), 2.74-2.59 (m, 1H), 2.39-2.21 (m, 1H), 1.77 (s, 1H), 1.53(s, 1H), 0.93 (t, J = 7.3 Hz, 3H). 750.9 0.5 169

1H NMR (400 MHz, DMSO-d6) δ 10.62 (s, 1H), 9.16 (d, J = 8.1 Hz, 1H),8.84 (dd, J = 4.1, 1.6 Hz, 1H), 8.65 (dd, J = 8.7, 1.7 Hz, 1H), 8.16 (d,J = 1.6 Hz, 1H), 7.97-7.86 (m, 3H), 7.67-7.58 (m, 5H), 7.58- 7.50 (m,4H), 4.76 (q, J = 5.3, 4.7 Hz, 1H), 3.43 (s, 2H). 612.2 88.6 170

1H NMR (400 MHz, DMSO-d6) δ 8.83 (dd, J = 4.1, 1.6 Hz, 1H), 8.71 (d, J =8.0 Hz, 1H), 8.64 (dd, J = 8.7, 1.7 Hz, 1H), 8.15 (d, J = 1.6 Hz, 1H),7.90 (dd, J = 7.9, 1.7 Hz, 1H), 7.67-7.52 (m, 4H), 6.58 (d, J = 9.0 Hz,1H), 6.34 (d, J = 12.1 Hz, 2H), 4.69 (d, J = 12.1 Hz, 1H), 3.89 (d, J =21.4 Hz, 1H), 3.72 (s, 1H), 3.42 (s, 1H), 1.81 (s, 4H), 1.66 (s, 2H),1.40 (s, 3H). 625.2 93.7 171

1H NMR (400 MHz, DMSO-d6) δ 8.96 (d, J = 7.8 Hz, 1H), 8.83 (d, J = 4.2Hz, 1H), 8.67 (s, 1H), 7.64 (s, 1H), 7.58 (t, J = 7.3 Hz, 1H), 7.45 (d,J = 6.8 Hz, 1H), 6.76 (dd, J = 11.6, 4.1 Hz, 2H), 6.55 (s, 1H), 4.87 (d,J = 9.2 Hz, 1H), 4.71 (td, J = 8.9, 4.5 Hz, 1H), 4.17 (d, J = 12.7 Hz,1H), 3.78 (d, J = 13.7 Hz, 1H), 3.74-3.57 (m, 1H), 3.57- 3.34 (m, 5H),2.82 (t, J = 11.7 Hz, 1H), 2.53 (s, 3H), 1.20 (d, J = 6.6 Hz, 1H), 1.15(d, J = 6.1 Hz, 3H). 713.0 0.5 172

1H NMR (400 MHz, DMSO-d6) δ 8.93 (dd, J = 7.9, 3.4 Hz, 1H), 8.82 (d, J =4.2 Hz, 1H), 8.65 (s, 1H), 7.69-7.61 (m, 1H), 7.58 (t, J = 7.4 Hz, 1H),7.45 (d, J = 7.1 Hz, 1H), 6.64 (dd, J = 12.0, 4.1 Hz, 2H), 6.55 (d, J =1.3 Hz, 1H), 5.67 (ddd, J = 21.8, 10.0, 4.8 Hz, 1H), 5.25-5.10 (m, 2H),4.80 (s, 1H), 4.68 (td, J = 8.6, 7.7, 4.1 Hz, 1H), 4.00 (s, 2H), 3.71(td, J = 14.7, 4.5 Hz, 1H), 3.54-3.31 (m, 4H), 2.53 (s, 3H), 1.91 (ddd,J = 14.2, 10.2, 7.1 Hz, 1H), 1.78 (ddd, J = 14.1, 7.2, 4.1 Hz, 1H), 0.86(t, J = 7.3 Hz, 3H). 711.0 0.5 173

1H NMR (400 MHz, DMSO-d6) δ 8.80 (dd, J = 4.1, 1.6 Hz, 1H), 8.66 (d, J =8.6 Hz, 1H), 8.55 (s, 1H), 8.14 (dd, J = 1.6, 0.4 Hz, 1H), 7.88 (dd, J =7.9, 1.7 Hz, 1H), 7.68- 7.49 (m, 4H), 7.01 (d, J = 7.5 Hz, 1H), 6.23 (d,J = 11.2 Hz, 2H), 4.58 (s, 1H), 4.46-4.30 (m, 1H), 3.70 (s, 1H), 3.45(s, 1H), 2.42- 2.28 (m, 2H), 2.21 (dt, J = 15.3, 8.8 Hz, 1H), 1.68-1.49(m, 1H). 598.0 81.5 174

1H NMR (400 MHz, DMSO-d6) δ 11.19 (s, 1H), 8.99 (s, 1H), 8.83 (d, J =3.6 Hz, 1H), 8.66 (d, J = 8.4 Hz, 1H), 8.17 (d, J = 1.7 Hz, 1H), 7.91(d, J = 7.9 Hz, 1H), 7.72- 7.57 (m, 2H), 7.54 (d, J = 7.9 Hz, 1H), 7.18(s, 1H), 4.86 (s, 1H), 3.78-3.68 (m, 1H), 3.42 (s, 1H), 2.27 (d, J =11.2 Hz, 6H). 591.0 97.8 175

1H NMR (400 MHz, DMSO-d6) δ 9.12 (d, J = 8.1 Hz, 1H), 8.84 (dd, J = 4.1,1.6 Hz, 1H), 8.62 (dd, J = 8.7, 1.7 Hz, 1H), 8.17 (dd, J = 1.6, 0.4 Hz,1H), 7.91 (dd, J = 7.9, 1.7 Hz, 1H), 7.65-7.54 (m, 6H), 7.50- 7.42 (m,3H), 6.93 (d, J = 9.4 Hz, 2H), 6.45 (q, J = 6.6 Hz, 1H), 4.75-4.67 (m,1H), 3.81-3.67 (m, 1H), 3.44-3.29 (m, 1H). 666.1 97.1 176

1H NMR (400 MHz, DMSO-d6) δ 8.91 (d, J = 4.3 Hz, 1H), 8.79 (t, J = 10.4Hz, 2H), 7.78-7.69 (m, 2H), 7.64 (d, J = 7.4 Hz, 1H), 6.78 (d, J = 9.4Hz, 1H), 6.45 (d, J = 11.9 Hz, 2H), 4.78-4.58 (m, 1H), 4.30 (m, 1H),3.72 (dd, J = 14.5, 4.6 Hz, 1H), 3.55 (d, J = 1.3 Hz, 3H), 3.45 (dd, J =14.5, 9.7 Hz, 1H), 2.81 (q, J = 7.4 Hz, 2H), 2.66 (d, J = 7.3 Hz, 1H),1.76 (d, J = 11.7 Hz, 1H), 1.62-1.43 (m, 1H), 1.25 (t, J = 7.4 Hz, 3H),1.22- 1.08 (m, 3H), 0.93 (t, J = 7.3 Hz, 3H). 646.3 0.9 177

1H NMR (400 MHz, DMSO-d6) δ 9.26 (d, J = 8.2 Hz, 1H), 8.86 (d, J = 4.1Hz, 1H), 8.63 (d, J = 8.6 Hz, 1H), 7.67-7.59 (m, 1H), 7.57 (d, J = 7.5Hz, 1H), 7.48 (t, J = 8.4 Hz, 1H), 7.36-7.24 (m, 1H), 7.10 (t, J = 8.0Hz, 2H), 7.03 (dd, J = 12.9, 7.1 Hz, 1H), 4.74 (s, 1H), 4.61 (t, J = 7.0Hz, 1H), 3.79-3.70 (m, 1H), 3.42-3.33 (m, 2H), 2.22 (s, 3H), 1.74-1.62(m, 2H), 1.57 (d, J = 9.7 Hz, 1H), 1.51-1.42 (m, 1H). 539.0 28.0 178

1H NMR (400 MHz, DMSO-d6) δ 9.35 (d, J = 8.2 Hz, 1H), 8.84 (dd, J = 4.2,1.6 Hz, 1H), 8.74 (d, J = 5.4 Hz, 1H), 8.64 (dd, J = 8.7, 1.7 Hz, 1H),8.16 (d, J = 1.7 Hz, 1H), 7.90 (d, J = 8.2 Hz, 1H), 7.67- 7.60 (m, 3H),7.56 (dd, J = 8.1, 6.2 Hz, 3H), 4.79 (d, J = 7.6 Hz, 1H), 3.78 (s, 1H),3.50-3.32 (m, 3H), 3.24 (s, 3H), 2.65 (s, 1H), 2.31 (s, 1H). 593.6 37.1179

1H NMR (400 MHz, DMSO-d6) δ 9.13 (d, J = 8.3 Hz, 1H), 8.84 (dd, J = 4.2,1.6 Hz, 1H), 8.67 (dd, J = 8.7, 1.7 Hz, 1H), 8.17 (d, J = 1.6 Hz, 1H),7.92 (d, J = 7.8 Hz, 1H), 7.74-7.58 (m, 3H), 7.54 (d, J = 7.9 Hz, 1H),7.46 (s, 1H), 4.86 (s, 1H), 3.76 (dd, J = 14.3, 4.1 Hz, 1H), 3.39 (t, J= 12.7 Hz, 1H), 2.14 (ddd, J = 12.9, 8.3, 5.0 Hz, 1H), 1.19-0.98 (m,3H). 604.1 37.7 180

1H NMR (400 MHz, DMSO-d6) δ 8.90-8.81 (m, 2H), 8.74 (t, J = 7.8 Hz, 1H),7.74-7.64 (m, 1H), 7.61 (t, J = 7.5 Hz, 1H), 7.49 (dd, J = 7.4, 2.5 Hz,1H), 6.60-6.48 (m, 3H), 4.78-4.65 (m, 1H), 4.01- 3.84 (m, 2H), 3.79-3.57(m, 4H), 3.54-3.38 (m, 5H), 3.38-3.30 (m, 1H), 2.98 (td, J = 12.4, 3.9Hz, 1H), 1.04 (d, J = 6.6 Hz, 3H). 645.7 0.9 181

1H NMR (400 MHz, DMSO-d6) δ 12.93 (s, 1H), 8.94-8.85 (m, 1H), 8.81 (dd,J = 4.2, 1.5 Hz, 1H), 8.63 (d, J = 8.5 Hz, 1H), 7.61 (dd, J = 8.5, 4.2Hz, 1H), 7.57 (t, J = 6.9 Hz, 1H), 7.43 (dd, J = 7.4, 3.8 Hz, 1H), 6.63(dd, J = 11.8, 4.5 Hz, 2H), 6.55 (s, 1H), 4.69 (ddd, J = 12.8, 7.9, 4.0Hz, 1H), 3.90-3.83 (m, 1H), 3.72 (d, J = 11.8 Hz, 3H), 3.58 (s, 2H),3.49 (d, J = 2.0 Hz, 3H), 3.47-3.36 (m, 1H), 2.76- 2.64 (m, 1H), 2.53(d, J = 4.1 Hz, 3H), 2.44-2.29 (m, 1H), 1.13 (d, J = 6.2 Hz, 3H). 645.10.7 182

1H NMR (400 MHz, DMSO-d6) δ 8.93-8.86 (m, 1H), 8.83 (d, J = 8.0 Hz, 2H),8.00 (s, 1H), 7.83- 7.55 (m, 6H), 7.31 (ddd, J = 8.0, 7.1, 1.1 Hz, 1H),6.78 (d, J = 9.4 Hz, 1H), 6.44 (d, J = 11.6 Hz, 2H), 4.72-4.57 (m, 1H),4.30 (d, J = 8.3 Hz, 1H), 3.68 (s, 4H), 3.44 (dd, J = 14.5, 9.9 Hz, 1H),1.75 (ddd, J = 10.6, 7.4, 3.6 Hz, 1H), 1.51 (ddd, J = 13.7, 10.4, 7.1Hz, 1H), 0.91 (t, J = 7.3 Hz, 3H). 639.2 0.9 183

1H NMR (400 MHz, DMSO-d6) δ 8.78 (t, J = 7.7 Hz, 1H), 8.57 (s, 1H), 7.51(s, 2H), 7.40 (s, 1H), 6.81-6.67 (m, 1H), 6.56 (s, 1H), 6.44 (dd, J =11.4, 5.9 Hz, 2H), 4.66 (s, 1H), 4.29 (s, 1H), 3.67 (t, J = 16.9 Hz,1H), 3.50 (d, J = 2.6 Hz, 3H), 3.47-3.28 (m, 1H), 2.58 (s, 3H), 2.54 (s,3H), 1.87-1.65 (m, 1H), 1.53 (dt, J = 17.9, 7.3 Hz, 1H), 0.93 (t, J =7.3 Hz, 3H). 685.2 0.9 184

1H NMR (400 MHz, DMSO-d6) δ 9.24 (d, J = 8.5 Hz, 1H), 9.06 (d, J = 5.0Hz, 1H), 8.74 (t, J = 7.8 Hz, 1H), 8.10-7.93 (m, 1H), 7.84- 7.59 (m,2H), 6.77 (t, J = 9.0 Hz, 1H), 6.42 (dd, J = 16.1, 11.9 Hz, 2H), 5.75(d, J = 3.5 Hz, 1H), 4.81- 4.68 (m, 1H), 4.29 (s, 2H), 3.46- 3.30 (m,5H), 3.22 (s, 3H), 2.39 (d, J = 2.3 Hz, 3H), 1.81 (ddt, J = 28.3, 13.5,6.1 Hz, 3H), 1.60- 1.43 (m, 1H), 0.92 (td, J = 7.4, 2.8 Hz, 3H). 658.30.9 185

1H NMR (400 MHz, DMSO-d6) δ 8.86-8.65 (m, 3H), 7.75-7.49 (m, 6H), 6.76(d, J = 9.5 Hz, 1H), 6.43 (d, J = 11.4 Hz, 2H), 4.70 (dd, J = 9.2, 5.0Hz, 1H), 4.30 (d, J = 10.0 Hz, 1H), 3.65 (d, J = 2.4 Hz, 4H), 3.50 (dd,J = 14.5, 9.6 Hz, 1H), 2.04 (d, J = 8.8 Hz, 3H), 1.75 (ddd, J = 13.8,7.3, 3.3 Hz, 1H), 1.57-1.47 (m, 1H), 0.91 (t, J = 7.3 Hz, 3H). 671.2 1.0186

1H NMR (400 MHz, DMSO-d6) δ 8.98 (m, J = 25.3 Hz, 2H), 8.85 (d, J = 7.9Hz, 1H), 7.94 (d, J = 7.7 Hz, 1H), 7.91-7.81 (m, 1H), 7.74- 7.62 (m,2H), 6.79 (d, J = 9.4 Hz, 1H), 6.51-6.39 (m, 3H), 4.72- 4.64 (m, 1H),4.37-4.25 (m, 1H), 3.81-3.70 (m, 1H), 3.67 (d, J = 5.6 Hz, 3H),3.53-3.40 (m, 4H), 1.83-1.71 (m, 1H), 1.59-1.46 (m, 1H), 0.92 (t, J =7.3 Hz, 3H). 619.2 1.0 187

1H NMR (400 MHz, DMSO-d6) δ 8.81 (d, J = 7.0 Hz, 2H), 8.73 (s, 1H),7.79-7.45 (m, 6H), 6.84 (d, J = 9.1 Hz, 1H), 6.40 (d, J = 11.4 Hz, 2H),4.70 (dt, J = 8.8, 4.3 Hz, 1H), 4.54-4.48 (m, 1H), 3.68 (d, J = 4.9 Hz,1H), 3.64 (d, J = 2.3 Hz, 3H), 3.50 (dd, J = 14.5, 9.7 Hz, 1H), 2.04 (d,J = 8.2 Hz, 3H), 1.26 (d, J = 6.7 Hz, 3H). 657.2 1.1 188

1H NMR (400 MHz, DMSO-d6) δ 12.92 (s, 1H), 8.87 (d, J = 4.3 Hz, 1H),8.77 (q, J = 10.9, 9.3 Hz, 2H), 8.39 (s, 1H), 7.76-7.58 (m, 2H), 7.54(t, J = 7.7 Hz, 1H), 6.75 (dd, J = 9.3, 6.7 Hz, 1H), 6.43 (dd, J = 11.4,3.9 Hz, 2H), 4.71 (dt, J = 13.6, 9.5 Hz, 1H), 4.30 (d, J = 9.4 Hz, 1H),3.74 (ddd, J = 51.1, 14.5, 4.5 Hz, 1H), 3.51 (d, J = 2.2 Hz, 3H), 3.36(dd, J = 14.4, 10.5 Hz, 1H), 1.83 (d, J = 9.6 Hz, 3H), 1.77 (td, J =7.4, 4.2 Hz, 1H), 1.53 (h, J = 7.4 Hz, 1H), 0.92 (t, J = 7.3 Hz, 3H).671.3 1.2 189

1H NMR (400 MHz, DMSO-d6) δ 9.37 (d, J = 5.1 Hz, 1H), 9.05 (s, 1H), 8.96(d, J = 8.2 Hz, 1H), 8.92 (s, 1H), 8.19 (s, 1H), 8.11 (d, J = 5.1 Hz,1H), 7.83 (s, 1H), 7.78 (d, J = 7.6 Hz, 1H), 6.75 (d, J = 11.8 Hz, 2H),4.97-4.83 (m, 1H), 4.81- 4.70 (m, 1H), 4.16 (d, J = 12.8 Hz, 1H), 3.95(dd, J = 11.5, 3.7 Hz, 1H), 3.82 (dd, J = 14.4, 4.5 Hz, 1H), 3.73 (d, J= 12.9 Hz, 1H), 3.57 (d, J = 3.3 Hz, 1H), 3.54 (s, 1H), 3.53-3.47 (m,1H), 3.41 (d, J = 12.5 Hz, 1H), 3.29-3.16 (m, 1H), 2.54 (s, 1H). 656.215.1 190

1H NMR (400 MHz, DMSO-d6) δ 9.20 (s, 1H), 9.01 (d, J = 4.9 Hz, 1H), 8.94(d, J = 8.0 Hz, 1H), 7.98 (s, 1H), 7.83-7.70 (m, 2H), 6.74 (d, J = 12.0Hz, 2H), 6.48 (s, 1H), 5.00-4.88 (m, 1H), 4.78-4.69 (m, 1H), 3.79 (t, J= 12.8 Hz, 1H), 3.69 (s, 3H), 3.61 (d, J = 12.8 Hz, 1H), 3.52 (d, J =10.8 Hz, 1H), 3.45 (s, 3H), 3.02 (t, J = 12.2 Hz, 1H), 2.52 (s, 3H),2.02-1.89 (m, 1H), 1.86-1.68 (m, 2H), 1.67- 1.42 (m, 3H). 659.7 1.2 191

1H NMR (400 MHz, DMSO-d6) δ 13.18-12.57 (s, 1H), 8.91 (dd, J = 7.9, 3.0Hz, 1H), 8.81 (s, 1H), 8.63 (s, 1H), 7.58 (m, J = 18.1, 10.7 Hz, 2H),7.43 (s, 1H), 6.62 (dd, J = 11.2, 3.9 Hz, 2H), 6.54 (s, 1H), 4.75-4.65(m, 1H), 3.93 (m, 2H), 3.71 (t, J = 12.9 Hz, 1H), 3.63- 3.54 (m, 1H),3.49 (d, J = 2.0 Hz, 3H), 3.47-3.37 (m, 1H), 3.34 (dd, J = 11.6, 5.0 Hz,1H), 3.27 (dd, J = 12.6, 3.6 Hz, 1H), 2.96 (dd, J = 12.5, 5.4 Hz, 1H),2.53 (s, 3H), 1.15 (d, J = 6.4 Hz, 3H), 1.01 (d, J = 6.3 Hz, 3H). 659.41.3 192

1H NMR (400 MHz, DMSO-d6) δ 9.16 (s, 1H), 8.99 (d, J = 8.0 Hz, 1H), 8.86(d, J = 4.1 Hz, 1H), 8.79 (d, J = 6.6 Hz, 1H), 8.68 (d, J = 8.6 Hz, 1H),8.19 (s, 1H), 7.87 (d, J = 6.5 Hz, 1H), 7.72 (d, J = 7.3 Hz, 1H),7.69-7.61 (m, 2H), 6.77 (d, J = 11.7 Hz, 2H), 4.96-4.84 (m, 1H), 4.70(dt, J = 8.4, 5.3 Hz, 1H), 4.17 (d, J = 12.7 Hz, 1H), 3.96 (dd, J =11.4, 3.7 Hz, 1H), 3.79-3.75 (m, 1H), 3.73 (m, 4H), 3.6-3.55 (m, 1H),3.45 (dd, J = 15.3, 10.7 Hz, 2H), 3.24 (t, J = 12.2 Hz, 1H). 668.2 1.4193

1H NMR (400 MHz, DMSO-d6) δ 9.01-8.91 (m, 1H), 8.80 (s, 1H), 8.73 (d, J= 5.5 Hz, 1H), 8.64 (t, J = 7.6 Hz, 1H), 7.62 (s, 3H), 7.46 (s, 1H),6.82-6.70 (m, 2H), 4.91 (d, J = 9.4 Hz, 1H), 4.72 (dd, J = 22.6, 8.8 Hz,1H), 4.40 (d, J = 8.1 Hz, 2H), 4.16 (d, J = 12.8 Hz, 1H), 3.95 (d, J =11.1 Hz, 1H), 3.73 (q, J = 14.1, 12.5 Hz, 2H), 3.61-3.35 (m, 3H), 3.24(t, J = 12.3 Hz, 1H), 1.42 (t, J = 7.0 Hz, 3H). 699.3 1.4 194

1H NMR (400 MHz, DMSO-d6) δ 8.98 (d, J = 8.0 Hz, 1H), 8.86 (dd, J = 4.3,1.5 Hz, 1H), 8.66 (d, J = 8.6 Hz, 1H), 7.95 (d, J = 9.0 Hz, 1H),7.73-7.54 (m, 3H), 6.74 (d, J = 11.7 Hz, 3H), 4.90 (dt, J = 8.8, 5.3 Hz,1H), 4.75-4.56 (m, 1H), 4.15 (d, J = 12.7 Hz, 1H), 3.94 (dd, J = 11.5,3.8 Hz, 1H), 3.80- 3.63 (m, 2H), 3.62-3.46 (m, 1H), 3.41 (dd, J = 12.9,7.8 Hz, 2H), 3.21 (t, J = 12.3 Hz, 1H). 670.2 1.4 195

1H NMR (400 MHz, DMSO-d6) δ 9.38 (d, J = 8.2 Hz, 1H), 9.01 (d, J = 8.5Hz, 1H), 8.84 (dd, J = 4.1, 1.6 Hz, 1H), 8.64 (dd, J = 8.7, 1.6 Hz, 1H),8.16 (d, J = 1.6 Hz, 1H), 7.91 (d, J = 7.9 Hz, 1H), 7.68- 7.59 (m, 5H),7.56 (d, J = 7.9 Hz, 1H), 4.81 (d, J = 7.9 Hz, 2H), 3.79 (s, 1H), 3.41(s, 1H), 2.65 (s, 1H), 2.31 (d, J = 1.9 Hz, 1H), 2.06 (s, 1H), 1.34 (d,J = 7.1 Hz, 3H). 631.2 62.3 196

1H NMR (400 MHz, DMSO-d6) δ 9.33 (dd, J = 15.0, 8.3 Hz, 1H), 8.93 (d, J= 4.2 Hz, 1H), 8.73 (d, J = 9.0 Hz, 1H), 8.12 (s, 1H), 7.86- 7.79 (m,2H), 7.77-7.65 (m, 3H), 7.53 (d, J = 8.3 Hz, 1H), 7.51- 7.37 (m, 4H),4.87 (td, J = 9.2, 4.7 Hz, 1H), 3.77 (dd, J = 14.4, 4.7 Hz, 1H), 3.46(dd, J = 14.5, 10.0 Hz, 1H). 533.1 63.1 197

1H NMR (400 MHz, DMSO-d6) δ 9.35 (d, J = 8.3 Hz, 1H), 8.83 (dd, J = 4.1,1.6 Hz, 1H), 8.64 (d, J = 7.2 Hz, 1H), 8.60 (d, J = 4.2 Hz, 1H), 8.16(d, J = 1.6 Hz, 1H), 7.91 (d, J = 7.8 Hz, 1H), 7.66-7.62 (m, 1H), 7.61(d, J = 2.8 Hz, 2H), 7.56 (d, J = 7.9 Hz, 1H), 7.51 (d, J = 8.2 Hz, 2H),4.79 (s, 1H), 2.83 (d, J = 4.0 Hz, 1H), 2.65 (s, 1H), 2.31 (s, 1H), 0.68(dd, J = 7.0, 4.7 Hz, 2H), 0.61-0.48 (m, 2H). 575.0 63.4 198

1H NMR (400 MHz, DMSO-d6) δ 8.96 (d, J = 8.3 Hz, 1H), 8.81 (d, J = 4.1Hz, 1H), 8.63 (d, J = 8.7 Hz, 1H), 7.59 (ddd, J = 15.7, 8.0, 4.0 Hz,2H), 7.44 (dd, J = 7.4, 3.9 Hz, 1H), 6.76 (dd, J = 11.6, 4.3 Hz, 3H),6.54 (s, 1H), 4.87 (d, J = 8.8 Hz, 1H), 4.74-4.64 (m, 1H), 4.17 (d, J =12.7 Hz, 1H), 3.82-3.57 (m, 4H), 3.53 (d, J = 12.4 Hz, 1H), 3.49 (d, J =2.1 Hz, 4H), 3.47- 3.36 (m, 1H), 3.15-3.04 (m, 1H), 2.82 (t, J = 11.6Hz, 1H), 2.54 (d, J = 3.7 Hz, 4H), 1.18 (d, J = 7.3 Hz, 1H), 1.15 (d, J= 6.1 Hz, 4H). 713.3 1.4 199

1H NMR (400 MHz, DMSO-d6) δ 13.16-12.62 (s, 1H), 8.87 (s, 1H), 8.79 (t,J = 7.3 Hz, 1H), 7.99 (s, 1H), 7.76-7.45 (m, 4H), 6.76 (dd, J = 9.4, 5.7Hz, 1H), 6.43 (dd, J = 11.4, 4.5 Hz, 2H), 4.71 (m, 1H), 4.30 (m, 1H),3.73 (dd, J = 51.5, 14.6 Hz, 1H), 3.42 (m, J = 2.2 Hz, 4H), 1.75 (d, J =9.1 Hz, 4H), 1.60- 1.43 (m, 1H), 0.92 (t, J = 7.3 Hz, 3H). 621.3 1.5 200

1H NMR (400 MHz, DMSO-d6) δ 8.96-8.84 (m, 2H), 8.79 (t, J = 8.1, 6.7 Hz,1H), 8.14 (d, J = 2.2 Hz, 1H), 7.85-7.73 (m, 1H), 7.68 (dd, J = 12.8,7.4 Hz, 1H), 7.60 (t, J = 7.2 Hz, 1H), 6.76 (dd, J = 9.5, 5.0 Hz, 1H),6.43 (dd, J = 11.4, 2.8 Hz, 2H), 4.72 (ddt, J = 15.3, 10.4, 4.6 Hz, 1H),4.30 (q, J = 8.8 Hz, 1H), 3.83 (dd, J = 14.3, 4.3 Hz, 1H), 3.56-3.33 (m,4H), 1.83 (d, J = 10.6 Hz, 3H), 1.80-1.70 (m, 1H), 1.60-1.45 (m, 1H),0.92 (t, J = 7.3 Hz, 3H). 637.2 1.5 201

1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J = 8.1 Hz, 1H), 7.66 (s, 3H), 6.77(d, J = 10.2 Hz, 3H), 6.44 (d, J = 11.6 Hz, 2H), 4.70 (s, 1H), 4.54 (s,2H), 4.41-4.24 (m, 1H), 3.73 (d, J = 13.5 Hz, 1H), 3.67-3.52 (m, 6H),3.52-3.25 (m, 1H), 1.76 (dd, J = 7.3, 3.9 Hz, 1H), 1.62-1.40 (m, 1H),1.21 (t, J = 7.0 Hz, 3H), 0.92 (t, J = 7.3 Hz, 3H). 676.2 1.5 202

1H NMR (400 MHz, DMSO-d6) δ 9.03 (t, J = 9.0 Hz, 1H), 8.99- 8.92 (m,1H), 8.90 (d, J = 8.1 Hz, 1H), 7.86 (ddd, J = 17.7, 8.7, 5.0 Hz, 1H),7.72 (dd, J = 15.8, 7.4 Hz, 1H), 7.62 (t, J = 9.0, 7.4 Hz, 1H), 6.71 (d,J = 12.0 Hz, 2H), 6.24 (d, J = 2.4 Hz, 1H), 4.99- 4.86 (m, 1H),4.81-4.68 (m, 1H), 3.85 (dd, J = 14.3, 4.3 Hz, 1H), 3.73 (dd, J = 14.6,4.7 Hz, 1H), 3.65-3.49 (m, 2H), 3.48-3.36 (m, 4H), 3.01 (t, J = 12.3 Hz,1H), 2.43 (s, 3H), 2.02-1.90 (m, 1H), 1.86-1.67 (m, 3H), 1.67-1.42 (m,3H). 643.7 1.5 203

1H NMR (400 MHz, DMSO-d6) δ 13.08 (s, 1H), 9.28 (dd, J = 8.2, 2.8 Hz,1H), 8.93 (dd, J = 4.5, 2.4 Hz, 1H), 8.83 (s, 1H), 7.75 (ddt, J = 6.9,4.7, 1.5 Hz, 4H), 7.70-7.50 (m, 4H), 6.91-6.82 (m, 2H), 4.85- 4.72 (m,3H), 3.46 (d, J = 3.5 Hz, 3H), 3.22 (d, J = 2.7 Hz, 3H), 1.92 (d, J =9.6 Hz, 3H). 662.8 1.6 204

1H NMR (400 MHz, DMSO-d6) δ 13.19-12.63 (s, 1H), 8.89-8.76 (m, 2H), 8.63(s, 1H), 7.66-7.54 (m, 2H), 7.48-7.39 (m, 1H), 6.57 (d, J = 4.6 Hz, 1H),6.54 (s, 2H), 4.71 (d, J = 9.5 Hz, 1H), 3.93 (d, J = 7.1 Hz, 1H), 3.68(m, J = 4.4 Hz, 3H), 3.57-3.50 (m, 1H), 3.49 (d, J = 1.8 Hz, 3H),3.47-3.37 (m, 2H), 2.58 (d, J = 11.7 Hz, 1H), 2.53 (s, 3H), 1.16 (d, J =6.1 Hz, 3H), 1.02 (d, J = 6.5 Hz, 3H). 658.9 1.7 205

1H NMR (400 MHz, DMSO-d6) δ 9.01-8.88 (m, 3H), 7.96 (d, J = 8.0 Hz, 1H),7.88-7.69 (m, 4H), 7.64 (d, J = 8.6 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H),6.75 (dd, J = 11.6, 8.0 Hz, 2H), 4.97-4.70 (m, 2H), 4.16 (d, J = 12.7Hz, 1H), 4.00- 3.85 (m, 2H), 3.73 (d, J = 13.9 Hz, 2H), 3.64 (d, 3H),3.56 (t, J = 13.5, 7.5 Hz, 1H), 3.42 (d, J = 12.1 Hz, 1H), 3.30 (s, 3H),3.25 (t, J = 13.4 Hz, 1H). 697.3 1.7 206

1H NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H), 9.34 (s, 1H), 8.96 (d, J = 8.2Hz, 1H), 8.56 (dd, J = 9.1, 6.1 Hz, 1H), 8.27-8.07 (m, 2H), 7.98 (d, J =3.5 Hz, 1H), 7.80 (td, J = 8.9, 2.6 Hz, 1H), 6.73 (d, J = 11.7 Hz, 2H),4.94-4.78 (m, 2H), 4.15 (d, J = 12.7 Hz, 1H), 3.93 (dt, J = 13.7, 7.1Hz, 2H), 3.72 (d, J = 14.8 Hz, 2H), 3.61-3.50 (m, 2H), 3.39 (d, J = 13.1Hz, 1H), 3.21 (t, J = 15.5 Hz, 1H), 3.11 (s, 3H). 670.2 1.7 207

1H NMR (400 MHz, DMSO-d6) δ 8.88-8.80 (m, 2H), 8.71-8.62 (m, 1H), 8.27(s, 1H), 7.69-7.49 (m, 3H), 6.86 (d, J = 9.2 Hz, 1H), 6.43 (d, J = 11.5Hz, 2H), 4.70- 4.61 (m, 1H), 4.58-4.45 (m, 1H), 3.78 (s, 3H), 3.68 (s,3H), 3.49- 3.38 (m, 2H), 1.28 (d, J = 6.7 Hz, 3H). 606.2 1.7 208

1H NMR (400 MHz, DMSO-d6) δ 8.82 (dd, J = 12.6, 6.1 Hz, 2H), 8.63 (d, J= 8.7 Hz, 1H), 7.90 (d, J = 9.2 Hz, 1H), 7.68-7.50 (m, 3H), 6.77 (d, J =9.4 Hz, 1H), 6.43 (d, J = 11.5 Hz, 2H), 4.65 (td, J = 9.1, 4.5 Hz, 1H),4.30 (s, 1H), 3.71 (d, J = 14.4 Hz, 1H), 3.45-3.32 (m, 1H), 1.89-1.61(m, 1H), 1.66- 1.34 (m, 1H), 0.91 (t, J = 7.3 Hz, 3H). 642.1 1.8 209

1H NMR (400 MHz, DMSO-d6) δ 8.89 (d, J = 4.3 Hz, 1H), 8.78 (dd, J =20.1, 8.3 Hz, 2H), 7.79-7.67 (m, 2H), 7.62 (t, J = 3.7 Hz, 2H), 6.77 (d,J = 9.4 Hz, 1H), 6.43 (d, J = 11.5 Hz, 2H), 4.69-4.59 (m, 1H), 4.29 (d,J = 10.4 Hz, 1H), 3.71 (dd, J = 14.4, 4.6 Hz, 1H), 3.45 (s, 4H), 2.23(d, J = 0.9 Hz, 3H), 1.75 (ddd, J = 13.9, 7.3, 3.2 Hz, 1H), 1.51 (ddd, J= 13.7, 10.4, 7.2 Hz, 1H), 0.91 (t, J = 7.3 Hz, 3H). 604.2 1.9 210

1H NMR (400 MHz, DMSO-d6) δ 8.92 (dd, J = 4.4, 1.5 Hz, 1H), 8.80 (t, J =9.0 Hz, 2H), 8.51 (dt, J = 2.8, 1.4 Hz, 1H), 7.77-7.67 (m, 3H), 7.62 (d,J = 7.5 Hz, 1H), 6.78 (d, J = 9.4 Hz, 1H), 6.43 (d, J = 11.5 Hz, 2H),4.65 (ddd, J = 9.9, 8.0, 4.5 Hz, 1H), 4.28 (t, J = 8.9 Hz, 1H), 3.72(dd, J = 14.4, 4.5 Hz, 1H), 3.55 (s, 3H), 3.41 (dd, J = 14.5, 9.9 Hz,1H), 1.75 (dtt, J = 14.8, 7.4, 3.7 Hz, 1H), 1.51 (ddt, J = 17.7, 14.5,7.3 Hz, 1H), 0.90 (t, J = 7.3 Hz, 3H). 656.7 1.9 211

1H NMR (400 MHz, DMSO-d6) δ 8.98 (dd, J = 4.4, 1.5 Hz, 1H), 8.85- 8.79(m, 2H), 7.94 (s, 1H), 7.77 (dd, J = 8.5, 4.4 Hz, 1H), 7.72 (d, J = 7.4Hz, 1H), 7.64 (d, J = 7.4 Hz, 1H), 6.87 (d, J = 9.2 Hz, 1H), 6.43 (d, J= 11.5 Hz, 2H), 4.66 (ddd, J = 9.6, 8.1, 4.4 Hz, 1H), 4.51 (dq, J =14.7, 7.1 Hz, 1H), 3.73 (dd, J = 14.4, 4.5 Hz, 1H), 3.47-3.38 (m, 4H),3.26 (s, 3H), 1.28 (d, J = 6.7 Hz, 3H). 606.2 1.9 212

1H NMR (400 MHz, DMSO-d6) δ 8.99 (d, J = 8.3 Hz, 1H), 8.93 (dd, J = 4.2,1.6 Hz, 1H), 8.76 (dd, J = 8.7, 1.7 Hz, 1H), 8.54 (d, J = 5.8 Hz, 1H),7.93 (d, J = 5.8 Hz, 1H), 7.84 (d, J = 7.4 Hz, 1H), 7.76 (dd, J = 7.9,3.2 Hz, 2H), 6.74 (d, J = 11.8 Hz, 2H), 4.91 (dd, J = 8.8, 3.6 Hz, 1H),4.77 (ddd, J = 10.4, 8.3, 4.3 Hz, 1H), 4.17 (d, J = 12.7 Hz, 1H), 3.96(dd, J = 11.4, 3.8 Hz, 1H), 3.84 (dd, J = 14.1, 4.2 Hz, 1H), 3.73 (d, J= 12.8 Hz, 1H), 3.59-3.35 (m, 3H), 3.23 (t, J = 12.2 Hz, 1H), 2.60 (s,3H), 2.29 (s, 6H). 644.4 1.9 213

1H NMR (400 MHz, DMSO-d6) δ 8.89-8.78 (m, 2H), 8.66 (dd, J = 8.6, 1.6Hz, 1H), 8.17 (d, J = 1.6 Hz, 1H), 7.91 (dd, J = 7.9, 1.7 Hz, 1H),7.68-7.60 (m, 3H), 7.58 (d, J = 7.9 Hz, 1H), 6.60 (d, J = 12.0 Hz, 2H),4.77-4.66 (m, 1H), 3.75 (s, 1H), 3.68 (dd, J = 6.0, 4.1 Hz, 2H), 3.43(s, 1H), 3.19 (t, J = 5.1 Hz, 2H), 3.11 (s, 2H), 1.16 (s, 6H). 605.928.6 214

1H NMR (400 MHz, DMSO-d6) δ 12.98 (s, 1H), 8.84 (dd, J = 4.1, 1.6 Hz,1H), 8.76 (d, J = 7.9 Hz, 1H), 8.64 (dd, J = 8.6, 1.7 Hz, 1H), 8.17 (d,J = 1.7 Hz, 1H), 7.91 (dd, J = 7.9, 1.7 Hz, 1H), 7.67-7.55 (m, 4H), 7.25(d, J = 6.4 Hz, 1H), 6.12 (d, J = 11.3 Hz, 2H), 4.83 (t, J = 6.5 Hz,2H), 4.68 (d, J = 7.3 Hz, 1H), 4.55 (h, J = 6.5 Hz, 1H), 4.36 (t, J =6.0 Hz, 2H), 3.74 (s, 1H), 3.44 (qd, J = 7.0, 4.9 Hz, 1H). 563.8 28.6215

1H NMR (400 MHz, DMSO-d6) δ 9.27 (d, J = 8.1 Hz, 1H), 8.83 (d, J = 4.0Hz, 1H), 8.64 (s, 1H), 7.67- 7.53 (m, 3H), 7.53-7.44 (m, 2H), 7.33 (d, J= 13.3 Hz, 1H), 7.11 (t, J = 8.0 Hz, 2H), 4.74 (t, J = 9.1 Hz, 1H),3.78-3.71 (m, 33H), 3.70 (s, 3H), 3.38 (dd, J = 14.6, 10.0 Hz, 1H).548.6 29.0 216

1H NMR (400 MHz, DMSO-d6) δ 8.83 (dd, J = 4.2, 1.6 Hz, 1H), 8.80 (d, J =8.0 Hz, 1H), 8.64 (dd, J = 8.7, 1.7 Hz, 1H), 8.15 (dd, J = 1.6, 0.4 Hz,1H), 7.90 (dd, J = 7.9, 1.7 Hz, 1H), 7.67-7.59 (m, 3H), 7.57 (dd, J =7.9, 0.4 Hz, 1H), 6.56 (d, J = 12.3 Hz, 2H), 4.71 (m, 1H), 3.73 (s, 1H),3.44 (d, J = 13.2 Hz, 3H), 3.26-3.05 (m, 2H), 1.43 (d, J = 11.2 Hz, 4H),1.10 (s, 3H). 605.6 31.0 217

1H NMR (400 MHz, DMSO-d6) δ 8.88 (d, J = 7.8 Hz, 1H), 8.83 (d, J = 4.2Hz, 1H), 8.66 (d, J = 7.9 Hz, 1H), 7.64 (dd, J = 8.6, 4.3 Hz, 1H), 7.58(t, J = 7.0 Hz, 1H), 7.45 (dd, J = 7.5, 3.2 Hz, 1H), 6.62 (dd, J = 11.6,4.3 Hz, 2H), 6.55 (s, 1H), 4.71 (d, J = 10.4 Hz, 1H), 3.78- 3.63 (m,5H), 3.55-3.34 (m, 4H), 3.20 (t, J = 4.9 Hz, 4H), 2.53 (s, 3H). 631.22.0 218

1H NMR (400 MHz, Chloroform-d) δ 9.48-8.74 (m, 1H), 7.82-7.65 (m, 2H),7.56 (d, J = 7.4 Hz, 1H), 7.35 (d, J = 7.9 Hz, 1H), 7.26 (d, J = 0.8 Hz,3H), 6.91 (dt, J = 19.9, 8.1 Hz, 2H), 6.56 (d, J = 11.9 Hz, 1H), 5.04(t, J = 9.9 Hz, 1H), 3.94 (dd, J = 14.3, 6.2 Hz, 1H), 3.59 (d, J = 14.2Hz, 2H), 2.55 (d, J = 7.6 Hz, 3H). 546.0 2.1 219

1H NMR (400 MHz, DMSO-d6) δ 11.65 (s, 1H), 9.12 (d, J = 8.6 Hz, 1H),8.88 (s, 1H), 7.72 (d, J = 23.5 Hz, 3H), 7.67-7.43 (m, 2H), 6.77 (d, J =6.7 Hz, 2H), 6.50 (dd, J = 3.1, 1.9 Hz, 1H), 4.88 (d, J = 9.5 Hz, 1H),4.54 (s, 2H), 3.79 (d, J = 14.4 Hz, 1H), 3.67-3.51 (m, 8H), 3.43 (t, J =12.8 Hz, 1H), 1.21 (t, J = 7.0 Hz, 3H). 621.9 2.1 220

1H NMR (400 MHz, DMSO-d6) δ 8.88 (d, J = 8.1 Hz, 1H), 8.83 (dd, J = 4.1,1.6 Hz, 1H), 8.64 (dd, J = 8.6, 1.7 Hz, 1H), 8.15 (d, J = 1.6 Hz, 1H),7.90 (dd, J = 7.9, 1.7 Hz, 1H), 7.68-7.58 (m, 3H), 7.56 (d, J = 7.9 Hz,1H), 6.70 (d, J = 11.9 Hz, 2H), 4.71 (d, J = 7.7 Hz, 1H), 3.74 (s, 1H),3.45 (t, J = 5.8 Hz, 5H), 1.95 (tt, J = 13.7, 5.7 Hz, 5H). 611.5 45.2221

1H NMR (400 MHz, DMSO-d6) δ 13.04 (s, 1H), 9.24 (d, J = 8.2 Hz, 1H),8.83 (dd, J = 4.1, 1.6 Hz, 1H), 8.63 (dd, J = 8.7, 1.7 Hz, 1H), 8.15 (d,J = 1.6 Hz, 1H), 7.90 (dd, J = 7.9, 1.7 Hz, 1H), 7.63 (d, J = 13.6 Hz,3H), 7.56 (d, J = 7.9 Hz, 1H), 6.93 (d, J = 8.5 Hz, 2H), 4.81- 4.70 (m,1H), 3.84 (s, 2H), 3.76 (s, 1H), 2.14 (s, 3H). 548.1 48.2 222

1H NMR (400 MHz, DMSO-d6) δ 9.21 (d, J = 8.1 Hz, 1H), 8.84 (dd, J = 4.2,1.6 Hz, 1H), 8.64 (dd, J = 8.6, 1.6 Hz, 1H), 8.16 (dd, J = 1.6, 0.4 Hz,1H), 7.91 (dd, J = 7.9, 1.6 Hz, 1H), 7.68-7.58 (m, 3H), 7.56 (dd, J =7.9, 0.4 Hz, 1H), 7.48 (td, J = 8.4, 6.5 Hz, 1H), 7.15 (t, J = 8.6 Hz,1H), 7.11-7.01 (m, 1H), 6.90 (s, 1H), 4.77 (s, 1H), 3.73 (s, 1H), 3.41(s, 1H). 540.1 48.3 223

1H NMR (400 MHz, DMSO-d6) δ 8.97 (t, J = 7.8 Hz, 1H), 8.83- 8.76 (m,1H), 8.71 (d, J = 5.0 Hz, 1H), 8.65 (t, J = 7.7 Hz, 1H), 7.67- 7.54 (m,4H), 6.76 (dd, J = 11.6, 7.8 Hz, 2H), 4.91 (d, J = 9.3 Hz, 1H), 4.70 (d,J = 14.6 Hz, 1H), 4.16 (d, J = 12.7 Hz, 1H), 3.95 (dd, J = 11.6, 3.7 Hz,1H), 3.75 (t, J = 14.8 Hz, 2H), 3.62-3.35 (m, 3H), 3.23 (t, J = 12.3 Hz,1H), 2.59 (q, J = 2.3 Hz, 3H). 669.6 2.2 224

1H NMR (400 MHz, DMSO-d6) δ 13.08 (s, 1H), 9.31 (d, J = 8.1 Hz, 1H),8.86 (d, J = 4.3 Hz, 2H), 7.93- 7.70 (m, 5H), 7.62 (dd, J = 8.7, 6.9 Hz,3H), 6.89 (d, J = 8.1 Hz, 2H), 6.76 (d, J = 4.0 Hz, 2H), 4.85- 4.70 (m,1H), 4.78 (s, 2H), 4.54 (s, 2H), 3.84-3.67 (m, 1H), 3.58 (q, J = 7.0 Hz,2H), 3.56 (s, 3H), 3.55 (s, 3H), 3.43 (dd, J = 14.7, 10.1 Hz, 1H), 1.21(t, J = 7.0 Hz, 3H). 705.4 2.2 225

1H NMR (400 MHz, DMSO-d6) δ 11.41 (d, J = 2.3 Hz, 1H), 9.03 (d, J = 8.3Hz, 1H), 8.84 (dd, J = 4.1, 1.6 Hz, 1H), 8.74-8.61 (m, 1H), 8.17 (d, J =1.7 Hz, 1H), 7.92 (s, 1H), 7.76-7.45 (m, 4H), 7.20 (d, J = 0.9 Hz, 1H),6.10 (s, 1H), 3.74 (dd, J = 14.3, 4.1 Hz, 1H), 3.49- 3.31 (m, 1H), 2.01(td, J = 8.4, 4.2 Hz, 1H), 1.05-0.91 (m, 2H), 0.79 (ddd, J = 6.4, 5.3,3.9 Hz, 2H). 605.2 53.7 226

1H NMR (400 MHz, DMSO-d6) δ 8.93 (s, 1H), 8.87 (d, J = 8.1 Hz, 1H), 8.81(s, 1H), 7.74 (s, 1H), 7.70-7.51 (m, 2H), 6.75 (dd, J = 11.6, 4.2 Hz,2H), 4.70 (q, J = 12.2, 9.9 Hz, 1H), 4.19 (d, J = 15.1 Hz, 1H), 4.08 (d,J = 14.7 Hz, 1H), 3.87-3.62 (m, 1H), 3.57-3.30 (m, 5H), 3.30-3.14 (m,5H), 3.14- 2.94 (m, 2H), 1.92 (d, J = 9.6 Hz, 3H), 1.18 (d, J = 6.7 Hz,3H). 656.2 1.1 227

1H NMR (400 MHz, DMSO-d6) δ 8.96 (d, J = 7.9 Hz, 1H), 8.86- 8.77 (m,1H), 8.62 (d, J = 8.7 Hz, 1H), 7.67-7.53 (m, 2H), 7.43 (d, J = 7.2 Hz,1H), 6.83-6.70 (m, 2H), 6.54 (s, 1H), 4.86 (d, J = 9.3 Hz, 1H), 4.70 (d,J = 10.6 Hz, 1H), 3.94 (dd, J = 11.5, 3.6 Hz, 1H), 3.87 (s, 1H), 3.68(dd, J = 14.7, 4.3 Hz, 1H), 3.61 (t, J = 11.0 Hz, 1H), 3.48 (d, J = 2.2Hz, 3H), 3.43 (d, J = 14.6 Hz, 1H), 3.08 (t, J = 12.2 Hz, 1H), 2.52 (s,5H), 2.46 (s, 1H), 1.36-1.17 (m, 3H). 712.7 1.1 228

1H NMR (400 MHz, DMSO-d6) δ 11.47 (s, 1H), 9.05 (d, J = 8.4 Hz, 1H),8.85 (dd, J = 4.1, 1.6 Hz, 1H), 8.67 (dd, J = 8.7, 1.7 Hz, 1H), 8.17 (d,J = 1.6 Hz, 1H), 7.92 (d, J = 7.9 Hz, 1H), 7.79-7.50 (m, 4H), 7.36 (d, J= 0.6 Hz, 1H), 6.05 (d, J = 1.9 Hz, 1H), 4.86 (s, 1H), 3.75 (dd, J =14.4, 4.1 Hz, 1H), 3.52- 3.31 (m, 1H), 2.12-1.98 (m, 1H), 1.07-0.89 (m,2H), 0.89-0.70 (m, 2H). 604.9 57.8 229

1H NMR (400 MHz, DMSO-d6) δ 8.91-8.77 (m, 2H), 8.63 (dd, J = 8.7, 1.7Hz, 1H), 8.15 (dd, J = 1.6, 0.4 Hz, 1H), 7.90 (dd, J = 7.9, 1.7 Hz, 1H),7.61 (s, 2H), 7.57 (dd, J = 7.9, 0.4 Hz, 1H), 7.50 (s, 1H), 6.29 (d, J =11.2 Hz, 2H), 4.68 (s, 1H), 3.73 (s, 1H), 3.40 (s, 1H), 1.46- 1.30 (m,2H), 1.03 (s, 2H). 615.2 60.5 230

1H NMR (400 MHz, DMSO-d6) δ 8.72 (d, 1H), 8.67 (d, J = 8.7 Hz, 1H), 8.09(s, 1H), 7.54-7.43 (m, 2H), 7.33 (d, J = 7.3 Hz, 1H), 6.72 (d, J = 12.1Hz, 2H), 6.51 (s, 1H), 4.99-4.83 (m, 1H), 4.46-4.31 (m, 1H), 3.72-3.56(m, 2H), 3.52- 3.39 (m, 4H), 3.32 (s, 3H), 3.02 (t, J = 12.2 Hz, 1H),1.95 (d, J = 14.5 Hz, 1H), 1.87-1.67 (m, 2H), 1.66-1.44 (m, 3H). 697.32.2 231

1H NMR (400 MHz, DMSO-d6) δ 8.97 (t, J = 7.2 Hz, 1H), 8.90 (d, J = 8.8Hz, 1H), 8.01 (dd, J = 8.8, 6.1 Hz, 1H), 7.72 (dd, J = 10.6, 7.3 Hz,1H), 7.60 (t, J = 7.6 Hz, 1H), 6.75 (dd, J = 11.5, 3.9 Hz, 2H), 6.57 (s,1H), 4.91 (d, J = 9.1 Hz, 1H), 4.74 (s, 1H), 4.16 (d, J = 12.7 Hz, 1H),4.01-3.90 (m, 1H), 3.85- 3.64 (m, 2H), 3.63-3.37 (m, 6H), 3.23 (t, J =12.3 Hz, 1H), 2.54 (s, 3H). 767.2 0.9 232

1H NMR (400 MHz, DMSO-d6) δ 8.91 (d, J = 3.9 Hz, 1H), 8.81 (d, J = 8.0Hz, 1H), 8.68 (s, 1H), 7.89 (s, 1H), 7.66 (dd, J = 12.4, 5.9 Hz, 2H),7.62-7.47 (m, 7H), 6.52 (d, J = 11.2 Hz, 2H), 5.79-5.70 (m, 1H), 4.60(td, J = 9.2, 4.4 Hz, 1H), 3.67 (dd, J = 14.5, 4.4 Hz, 1H), 3.38 (s,3H), 3.24 (s, 3H). 702.1 0.9 233

1H NMR (400 MHz, DMSO-d6) δ 12.92 (br s, 1H), 8.95 (t, J = 9.3 Hz, 1H),8.78 (d, J = 15.1 Hz, 2H), 8.63 (s, 1H), 7.70 (s, 1H), 7.60 (s, 3H),6.76 (t, J = 10.6 Hz, 2H), 4.91 (d, J = 9.4 Hz, 1H), 4.69 (d, J = 7.4Hz, 1H), 4.27 (s, 1H), 4.16 (d, J = 12.7 Hz, 1H), 3.99-3.91 (m, 1H),3.73 (d, J = 13.0 Hz, 2H), 3.61-3.35 (m, 3H), 3.23 (t, J = 12.2 Hz, 1H),0.96 (d, J = 6.1 Hz, 2H), 0.81 (q, J = 10.9, 9.6 Hz, 2H). 711.2 2.2 234

1H NMR (400 MHz, DMSO-d6) δ 8.92 (d, J = 4.4 Hz, 1H), 8.78 (d, J = 7.9Hz, 1H), 7.73 (s, 1H), 7.69- 7.52 (m, 2H), 6.76 (d, J = 9.4 Hz, 1H),6.41 (d, J = 11.5 Hz, 2H), 4.68 (td, J = 9.0, 8.5, 4.6 Hz, 1H), 4.29 (s,1H), 3.66 (dd, J = 14.3, 4.8 Hz, 1H), 3.54-3.39 (m, 4H), 3.22 (d, J =2.4 Hz, 3H), 1.92 (d, J = 10.3 Hz, 3H), 1.75 (ddd, J = 13.8, 7.2, 3.2Hz, 1H), 1.50 (ddd, J = 13.8, 10.4, 7.2 Hz, 1H), 0.90 (t, J = 7.3 Hz,3H). 634.2 2.3 235

1H NMR (400 MHz, DMSO-d6) δ 11.54 (s, 1H), 9.06 (d, J = 8.5 Hz, 1H),8.84 (s, 1H), 7.71 (s, 2H), 7.50 (dd, J = 3.2, 2.4 Hz, 1H), 7.40 (d, J =0.9 Hz, 1H), 6.75 (d, J = 6.2 Hz, 2H), 6.44 (d, J = 2.9 Hz, 1H), 4.88(s, 1H), 4.54 (s, 2H), 3.76 (d, J = 14.1 Hz, 1H), 3.67- 3.49 (m, 8H),3.41 (t, J = 12.7 Hz, 1H), 1.21 (t, J = 7.0 Hz, 3H). 622.4 2.3 236

1H NMR (400 MHz, DMSO-d6) δ 8.93-8.73 (m, 2H), 8.62 (t, J = 8.7 Hz, 1H),7.59 (dd, J = 11.1, 5.2 Hz, 3H), 6.76 (t, J = 8.9 Hz, 1H), 6.45 (dd, J =11.6, 7.8 Hz, 2H), 4.68 (m, 1H), 4.31 (s, 3H), 3.80- 3.59 (m, 1H),3.54-3.32 (m, 1H), 2.54 (s, 3H), 2.46 (s, 3H), 2.35 (s, 3H), 1.76 (s,1H), 1.52 (s, 1H), 0.92 (t, J = 7.3 Hz, 3H). 669.2 2.6 237

1H NMR (400 MHz, DMSO-d6) δ 8.94 (s, 1H), 8.88 (d, J = 8.1 Hz, 1H), 7.77(s, 1H), 7.71-7.52 (m, 2H), 6.75 (dd, J = 11.7, 4.2 Hz, 2H), 4.72 (td, J= 14.3, 12.8, 6.6 Hz, 1H), 4.19 (d, J = 15.3 Hz, 1H), 4.08 (d, J = 14.9Hz, 1H), 3.76 (ddd, J = 51.1, 14.4, 4.4 Hz, 1H), 3.55-3.29 (m, 6H),3.27-3.14 (m, 5H), 3.14-2.97 (m, 2H), 1.93 (d, J = 10.5 Hz, 3H), 1.18(d, J = 6.7 Hz, 3H). 656.2 2.6 238

1H NMR (400 MHz, DMSO-d6) δ 8.91-8.73 (m, 2H), 8.64 (d, J = 8.6 Hz, 1H),7.91 (s, 1H), 7.66- 7.54 (m, 2H), 6.84 (d, J = 9.2 Hz, 1H), 6.75 (s,1H), 6.41 (d, J = 11.4 Hz, 2H), 4.65 (td, J = 9.0, 8.2, 4.5 Hz, 1H),4.49 (dt, J = 14.8, 7.4 Hz, 1H), 3.76-3.66 (m, 1H), 3.45- 3.33 (m, 1H),1.26 (d, J = 6.7 Hz, 3H). 628.1 2.8 239

1H NMR (400 MHz, DMSO-d6) δ 10.72 (s, 1H), 9.23 (d, J = 8.1 Hz, 1H),8.91 (dd, J = 4.2, 1.5 Hz, 1H), 8.71-8.55 (m, 2H), 7.71 (dd, J = 8.6,4.2 Hz, 1H), 7.60-7.41 (m, 5H), 7.12 (dd, J = 8.4, 7.6 Hz, 2H), 4.68(ddd, J = 9.6, 8.1, 4.6 Hz, 1H), 3.71-3.60 (m, 1H), 3.34 (dd, J = 14.4,9.7 Hz, 1H). 544.1 77.9 240

1H NMR (400 MHz, DMSO-d6) δ 11.51 (d, J = 2.2 Hz, 1H), 9.03 (d, J = 8.3Hz, 1H), 8.84 (dd, J = 4.1, 1.6 Hz, 1H), 8.66 (dd, J = 8.7, 1.7 Hz, 1H),8.16 (d, J = 1.7 Hz, 1H), 7.91 (d, J = 7.9 Hz, 1H), 7.72- 7.48 (m, 4H),7.37-7.15 (m, 6H), 6.17 (s, 1H), 4.85 (s, 1H), 4.07 (s, 2H), 3.75 (dd, J= 14.5, 4.2 Hz, 1H), 3.40 (dd, J = 14.4, 10.6 Hz, 1H). 655.2 79.2 241

1H NMR (400 MHz, DMSO-d6) δ 9.41 (d, J = 8.2 Hz, 1H), 8.84 (dd, J = 4.1,1.6 Hz, 1H), 8.64 (dd, J = 8.6, 1.6 Hz, 1H), 8.16 (d, J = 1.7 Hz, 1H),7.91 (d, J = 8.1 Hz, 1H), 7.68-7.42 (m, 5H), 4.98-4.59 (m, 1H), 2.58 (s,3H), 534.2 80.1 242

1H NMR (400 MHz, DMSO-d6) δ 8.95 (dd, J = 8.1, 4.0 Hz, 1H), 8.92- 8.83(m, 2H), 7.77 (ddd, J = 16.0, 8.5, 4.6 Hz, 1H), 7.67 (dd, J = 13.4, 7.4Hz, 1H), 7.63-7.52 (m, 2H), 6.74 (d, J = 11.8 Hz, 2H), 4.95-4.85 (m,1H), 4.74 (ddq, J = 13.1, 8.7, 4.5 Hz, 1H), 4.16 (d, J = 12.7 Hz, 1H),3.95 (dd, J = 11.4, 3.8 Hz, 1H), 3.83 (dd, J = 14.6, 4.3 Hz, 1H), 3.73(m, 1H), 3.45 (d, J = 2.2 Hz, 3H), 3.41-3.32 (m, 2H), 3.23 (t, J = 12.4Hz, 1H), 3.17 (s, 1H), 2.68 (d, J = 11.0 Hz, 6H), 1.80 (d, J = 10.7 Hz,3H). 674.3 2.8 243

1H NMR (400 MHz, DMSO-d6) δ 13.29-12.42 (s, 1H), 8.92 (dd, J = 7.9, 2.7Hz, 1H), 8.82 (s, 1H), 8.65 (s, 1H), 7.63 (s, 1H), 7.58 (t, J = 7.0 Hz,1H), 7.45 (s, 1H), 6.62 (dd, J = 11.3, 4.3 Hz, 2H), 6.55 (s, 1H), 4.70(q, J = 7.8, 6.1 Hz, 1H), 3.99- 3.88 (m, 2H), 3.78-3.64 (m, 1H),3.64-3.55 (m, 1H), 3.49 (d, J = 2.1 Hz, 3H), 3.47-3.37 (m, 1H), 3.34(dd, J = 11.6, 5.0 Hz, 1H), 3.27 (dd, J = 12.5, 3.6 Hz, 1H), 3.00-2.91(m, 1H), 2.53 (s, 3H), 1.15 (d, J = 6.4 Hz, 3H), 1.01 (d, J = 6.3 Hz,3H). 659.4 2.9 244

1H NMR (400 MHz, DMSO-d6) δ 8.93 (dd, J = 8.0, 4.1 Hz, 1H), 8.83 (d, J =4.2 Hz, 1H), 8.71-8.63 (m, 1H), 7.64 (dt, J = 9.1, 5.1 Hz, 1H), 7.57 (t,J = 7.2 Hz, 1H), 7.45 (dd, J = 7.3, 5.0 Hz, 1H), 6.55 (s, 1H), 6.25 (dd,J = 9.8, 4.1 Hz, 2H), 4.92 (p, J = 6.6 Hz, 1H), 4.71 (td, J = 8.6, 8.1,4.1 Hz, 1H), 4.08 (td, J = 8.3, 5.1 Hz, 1H), 3.81-3.64 (m, 2H), 3.49 (d,J = 2.2 Hz, 3H), 2.69- 2.57 (m, 1H), 2.53 (s, 3H), 2.39 (ddd, J = 14.6,11.9, 6.6 Hz, 1H). 669.3 2.9 245

1H NMR (400 MHz, DMSO-d6) δ 8.93 (d, J = 8.1 Hz, 1H), 8.84 (dd, J = 4.2,1.6 Hz, 1H), 8.66 (dd, J = 8.7, 1.7 Hz, 1H), 8.16 (d, J = 1.6 Hz, 1H),7.90 (dd, J = 7.9, 1.7 Hz, 1H), 7.68-7.59 (m, 3H), 7.57 (d, J = 7.9 Hz,1H), 6.75 (d, J = 11.6 Hz, 2H), 4.78-4.64 (m, 1H), 4.29 (ddd, J = 10.1,6.8, 3.1 Hz, 1H), 4.03 (dd, J = 10.7, 3.3 Hz, 1H), 3.92-3.82 (m, 1H),3.79-3.62 (m, 3H), 3.42 (s, 1H), 2.92-2.73 (m, 2H). 645.8 33.6 246

1H NMR (400 MHz, DMSO-d6) δ 11.55 (s, 1H), 9.06 (d, J = 8.3 Hz, 1H),8.84 (dd, J = 4.1, 1.6 Hz, 1H), 8.67 (dd, J = 8.6, 1.6 Hz, 1H), 8.16 (d,J = 1.6 Hz, 1H), 7.92 (d, J = 7.9 Hz, 1H), 7.74-7.45 (m, 4H), 7.41 (d, J= 0.9 Hz, 1H), 6.45 (s, 1H), 4.87 (s, 1H), 3.75 (dd, J = 14.4, 4.3 Hz,1H), 3.41 (dd, J = 14.5, 10.4 Hz, 1H). 563.2 34.3 247

1H NMR (400 MHz, DMSO-d6) δ 8.83 (dd, J = 4.2, 1.6 Hz, 1H), 8.80 (d, J =8.1 Hz, 1H), 8.64 (dd, J = 8.7, 1.7 Hz, 1H), 8.15 (d, J = 1.7 Hz, 1H),7.90 (dd, J = 7.9, 1.7 Hz, 1H), 7.66-7.59 (m, 3H), 7.57 (d, J = 7.9 Hz,1H), 6.73 (d, J = 10.2 Hz, 1H), 6.50 (d, J = 11.9 Hz, 2H), 4.69 (d, J =7.8 Hz, 1H), 4.37 (q, J = 8.2 Hz, 1H), 3.84 (td, J = 12.2, 4.0 Hz, 2H),3.73 (s, 1H), 3.40 (s, 1H), 3.26 (qd, J = 9.3, 8.0, 4.2 Hz, 2H),2.05-1.89 (m, 1H), 1.55 (d, J = 13.0 Hz, 2H), 1.49-1.33 (m, 2H). 674.435.2 248

1H NMR (500 MHz, DMSO-d6) δ 8.98 (d, J = 8.2 Hz, 1H), 8.88 (dd, J = 4.1,1.6 Hz, 1H), 8.79 (d, J = 5.4 Hz, 1H), 8.75 (dd, J = 8.7, 1.6 Hz, 1H),8.63 (s, 1H), 8.02 (s, 1H), 7.91 (d, J = 7.3 Hz, 1H), 7.77- 7.69 (m,2H), 6.73 (d, J = 11.7 Hz, 2H), 4.91 (dd, J = 8.7, 3.6 Hz, 1H), 4.78(ddd, J = 10.4, 8.3, 4.4 Hz, 1H), 4.16 (d, J = 12.7 Hz, 1H), 3.96 (dd, J= 11.6, 3.8 Hz, 1H), 3.82 (dd, J = 14.3, 4.4 Hz, 1H), 3.78-3.70 (m, 1H),3.60-3.51 (m, 1H), 3.51-3.38 (m, 2H), 3.23 (t, J = 12.5 Hz, 1H), 2.59(p, J = 6.9 Hz, 1H), 1.08 (dd, J = 6.9, 4.2 Hz, 6H). 629.5 3.0 249

1H NMR (400 MHz, DMSO-d6) δ 13.12-12.65 (s, 1H), 8.89-8.76 (m, 2H), 8.63(d, J = 8.4 Hz, 1H), 7.66-7.53 (m, 2H), 7.44 (d, J = 7.3 Hz, 1H), 6.57(d, J = 4.6 Hz, 1H), 6.54 (d, J = 5.1 Hz, 2H), 4.76- 4.63 (m, 1H), 3.93(d, J = 7.3 Hz, 1H), 3.75-3.63 (m, 3H), 3.55 (d, J = 6.8 Hz, 1H), 3.49(d, J = 1.9 Hz, 3H), 3.47-3.37 (m, 2H), 2.58 (d, J = 11.7 Hz, 1H), 2.53(s, 3H), 1.16 (d, J = 6.1 Hz, 3H), 1.02 (d, J = 6.6 Hz, 3H). 659.4 3.0250

1H NMR (400 MHz, DMSO-d6) δ 8.89 (dd, J = 8.0, 3.1 Hz, 1H), 8.82 (dd, J= 4.5, 1.5 Hz, 1H), 8.65 (d, J = 8.4 Hz, 1H), 7.63 (dt, J = 8.4, 4.2 Hz,1H), 7.61-7.53 (m, 1H), 7.49-7.39 (m, 1H), 6.62- 6.52 (m, 3H), 6.17 (tt,J = 56.2, 4.6 Hz, 1H), 4.69 (td, J = 8.6, 7.8, 4.0 Hz, 1H), 4.08 (s,1H), 3.89 (dd, J = 11.4, 3.6 Hz, 1H), 3.83 (d, J = 11.7 Hz, 1H), 3.71(td, J = 14.1, 4.4 Hz, 1H), 3.61 (d, J = 11.5 Hz, 1H), 3.55-3.35 (m,5H), 3.05 (td, J = 12.5, 3.8 Hz, 1H), 2.53 (s, 3H), 2.45-2.26 (m, 1H),1.84 (td, J = 18.7, 14.2 Hz, 1H). 695.2 3.1 251

1H NMR (400 MHz, DMSO-d6) δ 8.96 (d, J = 2.2 Hz, 1H), 8.86 (s, 1H), 8.82(d, J = 9.4 Hz, 1H), 7.78- 7.70 (m, 1H), 7.65 (t, J = 7.9 Hz, 1H), 7.49(t, J = 8.3 Hz, 1H), 6.77- 6.72 (m, 2H), 4.90 (q, J = 10.1 Hz, 1H),4.77-4.67 (m, 2H), 4.16 (d, J = 12.9 Hz, 1H), 3.95 (d, J = 8.3 Hz, 1H),3.88-3.81 (m, 1H), 3.77-3.70 (m, 1H), 3.66 (s, 1H), 3.58-3.51 (m, 1H),3.49 (d, J = 2.1 Hz, 3H), 3.45-3.36 (m, 2H), 3.30-3.17 (m, 1H), 2.43 (s,3H), 2.09 (s, 3H), 1.74 (d, J = 11.0 Hz, 3H). 658.2 3.1 252

1H NMR (400 MHz, DMSO-d6) δ 8.85-8.77 (m, 2H), 8.71 (d, J = 5.1 Hz, 1H),8.65 (t, J = 7.6 Hz, 1H), 7.68-7.54 (m, 4H), 6.77 (t, J = 7.6 Hz, 1H),6.45 (dd, J = 11.7, 5.7 Hz, 2H), 4.78-4.61 (m, 1H), 4.40-4.22 (m, 1H),3.83-3.64 (m, 1H), 3.53-3.33 (m, 1H), 2.59 (q, J = 2.3 Hz, 3H),1.86-1.69 (m, 1H), 1.62-1.43 (m, 1H), 0.92 (t, J = 7.3 Hz, 3H). 641.83.1 253

1H NMR (400 MHz, DMSO-d6) δ 8.80 (dd, J = 12.3, 5.4 Hz, 2H), 8.64 (s,1H), 7.74-7.51 (m, 2H), 7.44 (dd, J = 7.4, 3.7 Hz, 1H), 6.75 (dd, J =9.5, 5.2 Hz, 1H), 6.54 (s, 1H), 6.44 (dd, J = 11.4, 3.8 Hz, 2H), 4.68(s, 1H), 4.30 (s, 1H), 3.75-3.62 (m, 1H), 3.48 (d, J = 2.3 Hz, 3H),3.46-3.31 (m, 1H), 2.53 (s, 3H), 1.75 (s, 1H), 1.52 (ddd, J = 13.8,10.4, 7.0 Hz, 1H), 0.92 (t, J = 7.3 Hz, 3H). 671.2 3.2 254

1H NMR (400 MHz, DMSO-d6) δ 8.89 (dd, J = 7.8, 4.3 Hz, 1H), 8.85- 8.78(m, 1H), 8.64 (s, 1H), 7.60 (ddd, J = 17.6, 8.0, 4.3 Hz, 2H), 7.44 (dd,J = 7.3, 3.7 Hz, 1H), 6.66- 6.49 (m, 3H), 4.69 (d, J = 11.1 Hz, 1H),4.29 (s, 2H), 3.89 (dd, J = 11.4, 3.6 Hz, 1H), 3.85-3.59 (m, 3H),3.57-3.38 (m, 5H), 3.08 (td, J = 12.6, 3.8 Hz, 1H), 2.77 (ddd, J = 15.4,11.7, 8.2 Hz, 1H), 2.53 (s, 3H), 2.42-2.20 (m, 1H). 713.2 3.2 255

1H NMR (400 MHz, DMSO-d6) δ 9.03-8.89 (m, 2H), 8.81 (s, 1H), 7.78 (d, J= 25.5 Hz, 2H), 7.70- 7.61 (m, 1H), 6.77 (d, J = 11.7 Hz, 2H), 4.90 (d,J = 8.8 Hz, 1H), 4.69 (td, J = 9.0, 4.4 Hz, 1H), 4.16 (d, J = 12.7 Hz,1H), 3.95 (dd, J = 11.4, 3.7 Hz, 1H), 3.82-3.68 (m, 2H), 3.63-3.35 (m,6H), 3.24 (m, 1H), 2.42 (s, 3H), 2.34 (s, 3H). 646.2 3.4 256

1H NMR (400 MHz, DMSO-d6) δ 13.17-12.71 (s, 1H), 8.82 (dd, J = 15.0, 6.1Hz, 2H), 8.63 (dd, J = 10.8, 6.2 Hz, 3H), 7.92 (d, J = 10.4 Hz, 1H),7.73 (dd, J = 8.5, 4.2 Hz, 1H), 7.63 (d, J = 7.2 Hz, 1H), 7.56 (d, J =7.3 Hz, 2H), 6.76 (d, J = 9.4 Hz, 1H), 6.45 (d, J = 11.7 Hz, 2H),4.82-4.69 (m, 1H), 4.31 (m, 1H), 3.85-3.76 (m, 1H), 3.43 (dd, J = 14.6,10.1 Hz, 1H), 1.88-1.68 (m, 1H), 1.63-1.45 (m, 1H), 0.93 (t, J = 7.3 Hz,3H). 695.3 3.5 257

1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J = 4.3 Hz, 1H), 8.77- 8.62 (m,2H), 7.62 (dt, J = 24.9, 5.7 Hz, 2H), 7.45 (d, J = 7.3 Hz, 1H), 6.55 (s,1H), 6.33 (dd, J = 12.2, 4.5 Hz, 2H), 4.69 (tt, J = 9.1, 5.0 Hz, 1H),4.01 (d, J = 17.4 Hz, 2H), 3.96-3.86 (m, 2H), 3.78- 3.65 (m, 1H), 3.60(d, J = 10.9 Hz, 1H), 3.52-3.37 (m, 4H), 3.30 (d, J = 10.8 Hz, 1H), 2.53(s, 3H), 2.09-1.94 (m, 1H), 1.87 (d, J = 8.6 Hz, 2H), 1.74-1.59 (m, 1H).657.3 3.5 258

1H NMR (400 MHz, DMSO-d6) δ 9.34-9.18 (m, 1H), 8.81 (d, J = 8.1 Hz, 1H),8.55 (dd, J = 9.0, 6.1 Hz, 1H), 8.21-8.10 (m, 2H), 7.98- 7.87 (m, 1H),7.82-7.73 (m, 1H), 6.79-6.75 (m, 1H), 6.43 (d, J = 11.5 Hz, 2H),4.83-4.73 (m, 1H), 4.36-4.22 (m, 1H), 4.15 (d, J = 12.7 Hz, 1H), 3.93(dt, J = 13.7, 7.1 Hz, 2H), 3.72 (d, J = 14.8 Hz, 2H), 3.61-3.50 (m,2H), 3.39 (d, J = 13.1 Hz, 1H), 3.21 (t, J = 15.5 Hz, 1H), 3.09 (s, 3H),1.75 (d, J = 24.4 Hz, 1H), 1.56-1.44 (m, 1H), 0.91 (t, J = 7.3 Hz, 3H).642.2 3.6 259

1H NMR (400 MHz, DMSO-d6) δ 8.97 (d, J = 8.0 Hz, 1H), 8.94 (dd, J = 4.6,1.5 Hz, 1H), 8.86 (d, J = 8.3 Hz, 1H), 7.76 (dd, J = 14.9, 6.0 Hz, 2H),7.71 (s, 1H), 7.66 (d, J = 7.4 Hz, 1H), 6.76 (d, J = 11.8 Hz, 2H), 4.91(s, 1H), 4.69 (td, J = 8.8, 4.6 Hz, 1H), 4.16 (d, J = 12.7 Hz, 1H), 3.96(dd, J = 11.5, 3.8 Hz, 1H), 3.76 (s, 1H), 3.72 (m, 1H), 3.55 (d, J = 3.6Hz, 1H), 3.53 (s, 3H), 3.49-3.40 (m, 2H), 3.24 (t, J = 12.4 Hz, 1H),2.65 (s, 6H), 2.52 (s, 3H). 674.3 3.7 260

1H NMR (400 MHz, DMSO-d6) δ 12.93 (s, 1H), 8.97 (d, J = 8.0 Hz, 1H),8.77 (dd, J = 4.1, 1.5 Hz, 1H), 8.73 (s, 1H), 8.64 (dt, J = 8.7, 1.7 Hz,1H), 8.13 (d, J = 2.0 Hz, 1H), 7.66-7.54 (m, 3H), 6.76 (d, J = 11.7 Hz,2H), 4.96-4.85 (m, 1H), 4.71 (ddd, J = 9.8, 8.1, 4.5 Hz, 1H), 4.16 (d, J= 12.7 Hz, 1H), 3.95 (dd, J = 11.5, 3.8 Hz, 1H), 3.79-3.70 (m, 2H),3.62-3.49 (m, 1H), 3.44 (dd, J = 14.2, 10.4 Hz, 2H), 3.23 (t, J = 12.4Hz, 1H), 2.50 (s, 3H). 669.3 3.8 261

1H NMR (400 MHz, DMSO-d6) δ 9.40 (s, 1H), 9.30 (s, 1H), 8.94 (d, J = 8.3Hz, 1H), 8.79 (s, 1H), 8.10 (d, J = 6.8 Hz, 1H), 7.93 (d, J = 7.8 Hz,1H), 7.48 (s, 1H), 6.73 (d, J = 11.8 Hz, 2H), 4.93-4.83 (m, 1H),4.83-4.74 (m, 1H), 4.15 (d, J = 12.7 Hz, 1H), 3.92 (ddd, J = 25.6, 12.9,4.1 Hz, 2H), 3.75- 3.69 (m, 1H), 3.58 (s, 1H), 3.55 (d, J = 5.6 Hz, 1H),3.38 (s, 1H), 3.22 (t, J = 12.5 Hz, 1H), 2.65 (s, 6H). 617.3 4.0 262

1H NMR (400 MHz, DMSO-d6) δ 8.83 (dd, J = 4.1, 1.6 Hz, 1H), 8.71- 8.61(m, 2H), 8.15 (d, J = 1.6 Hz, 1H), 7.90 (dd, J = 7.9, 1.7 Hz, 1H),7.67-7.59 (m, 3H), 7.57 (d, J = 7.9 Hz, 1H), 6.21 (d, J = 12.0 Hz, 2H),4.73-4.62 (m, 1H), 3.82 (dt, J = 11.5, 3.5 Hz, 2H), 3.72 (s, 2H),3.51-3.33 (m, 4H), 1.81 (ddt, J = 12.5, 4.4, 2.1 Hz, 2H), 1.38-1.23 (m,2H). 591.8 30.6 263

1H NMR (400 MHz, DMSO-d6) δ 9.35 (d, J = 22.1 Hz, 2H), 8.98- 8.91 (m,2H), 8.87 (s, 1H), 8.13 (d, J = 9.6 Hz, 1H), 7.95 (d, J = 7.7 Hz, 1H),7.59 (d, J = 5.3 Hz, 1H), 6.73 (d, J = 11.8 Hz, 2H), 4.95- 4.76 (m, 2H),4.15 (d, J = 12.7 Hz, 1H), 3.99-3.84 (m, 2H), 3.77- 3.64 (m, 2H), 3.56(dd, J = 14.2, 10.5 Hz, 1H), 3.34 (s, 1H), 3.23 (d, J = 12.9 Hz, 1H),2.70 (s, 3H). 602.3 4.0 264

1H NMR (400 MHz, DMSO-d6) δ 8.85 (t, J = 10.3 Hz, 2H), 8.79- 8.71 (m,2H), 8.59 (dd, J = 8.4, 1.8 Hz, 1H), 7.80-7.67 (m, 4H), 7.67- 7.55 (m,2H), 6.78 (d, J = 9.4 Hz, 1H), 6.46 (d, J = 11.8 Hz, 2H), 4.74 (t, J =11.0 Hz, 1H), 4.31 (d, J = 10.3 Hz, 1H), 3.85-3.74 (m, 1H), 3.48 (dd, J= 14.5, 9.8 Hz, 1H), 1.76 (d, J = 8.2 Hz, 1H), 1.62- 1.46 (m, 1H), 0.93(t, J = 7.3 Hz, 3H). 626.7 4.1 265

1H NMR (400 MHz, DMSO-d6) δ 8.93 (d, J = 8.1 Hz, 1H), 8.83 (dd, J = 4.1,1.6 Hz, 1H), 8.64 (dd, J = 8.7, 1.7 Hz, 1H), 8.16 (d, J = 1.6 Hz, 1H),7.90 (dd, J = 7.9, 1.7 Hz, 1H), 7.67-7.57 (m, 3H), 7.56 (d, J = 7.9 Hz,1H), 6.75 (d, J = 11.6 Hz, 2H), 4.77-4.66 (m, 1H), 4.29 (dq, J = 6.7,3.3 Hz, 1H), 4.03 (dd, J = 10.9, 3.3 Hz, 1H), 3.86 (d, J = 12.2 Hz, 1H),3.75 (m, 1H), 3.69 (t, J = 10.4 Hz, 2H), 3.41 (s, 1H), 2.92-2.72 (m,2H). 760.0 68.8 266

1H NMR (400 MHz, DMSO-d6) δ 11.53 (s, 1H), 8.84 (dd, J = 4.1, 1.6 Hz,1H), 8.68 (dd, J = 8.4, 2.4 Hz, 2H), 8.16 (d, J = 1.6 Hz, 1H), 7.91 (dd,J = 7.9, 1.6 Hz, 1H), 7.74- 7.53 (m, 4H), 7.48 (t, J = 2.8 Hz, 1H), 7.34(d, J = 8.3 Hz, 1H), 6.98 (s, 1H), 6.47 (d, J = 3.0 Hz, 1H), 4.80 (ddd,J = 10.5, 8.2, 4.2 Hz, 1H), 3.79 (dd, J = 14.4, 4.1 Hz, 1H), 3.48 (dd, J= 14.4, 10.6 Hz, 1H). 530.6 72.2 267

1H NMR (400 MHz, DMSO-d6) δ 9.35 (d, J = 8.2 Hz, 1H), 8.87- 8.80 (m,1H), 8.74 (d, J = 7.5 Hz, 1H), 8.64 (d, J = 8.6 Hz, 1H), 8.16 (d, J =1.7 Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.66-7.60 (m, 2H), 7.58-7.53 (m,2H), 4.79 (s, 1H), 3.95-3.78 (m, 1H), 2.65 (s, 1H), 2.31 (s, 1H), 1.88(d, J = 10.1 Hz, 2H). 605.2 77.0 268

1H NMR (400 MHz, DMSO-d6) δ 8.93 (d, J = 4.5 Hz, 1H), 8.89- 8.76 (m,2H), 7.82-7.59 (m, 4H), 6.79 (d, J = 9.4 Hz, 1H), 6.45 (d, J = 11.9 Hz,2H), 4.67 (dt, J = 13.3, 6.3 Hz, 1H), 4.30 (s, 1H), 3.53 (s, 3H),3.49-3.38 (m, 2H), 2.64 (s, 6H), 2.52 (s, 3H), 1.84-1.68 (m, 1H),1.61-1.45 (m, 1H), 0.93 (t, J = 7.3 Hz, 3H). 646.3 4.3 269

1H NMR (400 MHz, DMSO-d6) δ 8.93-8.86 (m, 1H), 8.80 (t, J = 7.2 Hz, 1H),8.00 (dd, J = 8.8, 3.9 Hz, 1H), 7.71 (t, J = 8.1 Hz, 1H), 7.59 (t, J =7.4 Hz, 1H), 6.75 (dd, J = 9.5, 4.7 Hz, 1H), 6.56 (s, 1H), 6.43 (dd, J =11.3, 3.4 Hz, 2H), 4.71 (s, 1H), 4.31 (s, 1H), 3.84- 3.66 (m, 1H),3.58-3.33 (m, 4H), 2.54 (s, 3H), 1.87-1.70 (m, 1H), 1.52 (ddd, J = 13.8,10.1, 6.9 Hz, 1H), 0.92 (t, J = 7.3 Hz, 3H). 739.2 4.4 270

1H NMR (400 MHz, DMSO-d6) δ 8.98 (d, J = 8.0 Hz, 1H), 8.80 (dd, J = 4.2,1.6 Hz, 1H), 8.67 (dd, J = 8.7, 1.7 Hz, 1H), 8.20 (d, J = 8.2 Hz, 1H),7.67-7.53 (m, 4H), 6.76 (d, J = 11.7 Hz, 2H), 4.91 (dd, J = 8.8, 3.7 Hz,1H), 4.71 (ddd, J = 9.9, 8.0, 4.5 Hz, 1H), 4.16 (d, J = 12.7 Hz, 1H),3.95 (dd, J = 11.5, 3.8 Hz, 1H), 3.81-3.69 (m, 2H), 3.55 (td, J = 11.9,3.3 Hz, 1H), 3.45 (dd, J = 18.1, 11.9 Hz, 2H), 3.23 (t, J = 12.1 Hz,1H), 2.58 (s, 3H). 669.4 4.4 271

1H NMR (400 MHz, DMSO-d6) δ 13.10 (s, 1H), 9.02 (d, J = 8.3 Hz, 1H),8.90 (dd, J = 4.2, 1.6 Hz, 1H), 8.77 (dd, J = 8.7, 1.6 Hz, 1H), 8.73 (d,J = 5.9 Hz, 1H), 8.00-7.88 (m, 2H), 7.79-7.70 (m, 2H), 6.75 (d, J = 11.8Hz, 2H), 4.90 (td, J = 8.7, 3.6 Hz, 1H), 4.77 (ddd, J = 10.4, 8.3, 4.3Hz, 1H), 4.16 (d, J = 12.7 Hz, 1H), 3.96 (dd, J = 11.5, 3.8 Hz, 1H),3.84 (dd, J = 14.2, 4.3 Hz, 1H), 3.78-3.69 (m, 1H), 3.60- 3.37 (m, 3H),3.23 (t, J = 12.3 Hz, 1H), 2.63 (s, 3H), 2.06-2.01 (m, 3H). 615.2 4.5272

1H NMR (400 MHz, DMSO-d6) δ 8.87-8.76 (m, 1H), 8.63 (q, J = 7.1 Hz, 2H),7.70-7.52 (m, 2H), 7.52-7.34 (m, 1H), 6.55 (s, 1H), 6.29 (s, 1H), 6.17(dd, J = 11.9, 4.5 Hz, 2H), 4.74-4.63 (m, 1H), 3.80-3.59 (m, 1H), 3.49(d, J = 2.1 Hz, 3H), 3.47-3.35 (m, 1H), 3.20 (s, 1H), 2.53 (s, 3H), 1.50(ddd, J = 13.1, 7.3, 5.3 Hz, 2H), 1.37 (dp, J = 14.4, 7.4 Hz, 2H), 0.84(t, J = 7.4 Hz, 6H). 631.2 4.5 273

1H NMR (400 MHz, DMSO-d6) δ 8.97 (d, J = 8.0 Hz, 1H), 8.86 (d, J = 4.0Hz, 1H), 8.67 (d, J = 8.6 Hz, 1H), 7.66 (dd, J = 8.1, 4.0 Hz, 2H), 7.58(d, J = 7.4 Hz, 1H), 7.50 (s, 1H), 6.76 (d, J = 11.7 Hz, 2H), 4.90 (dt,J = 12.0, 6.0 Hz, 1H), 4.69 (td, J = 8.8, 8.3, 4.5 Hz, 1H), 4.17 (d, J =12.7 Hz, 1H), 3.96 (dd, J = 11.6, 3.8 Hz, 1H), 3.80- 3.66 (m, 2H), 3.56(s, 4H), 3.43 (m, 1H), 3.32-3.16 (m, 2H), 2.43 (s, 3H). 646.2 4.7 274

1H NMR (400 MHz, DMSO-d6) δ 8.93 (d, J = 8.1 Hz, 1H), 8.84 (d, J = 4.2Hz, 1H), 8.68 (d, J = 8.7 Hz, 1H), 7.64 (d, J = 3.5 Hz, 3H), 6.75 (d, J= 11.7 Hz, 2H), 4.90 (d, J = 9.4 Hz, 1H), 4.73 (td, J = 9.0, 4.3 Hz,1H), 4.16 (d, J = 12.7 Hz, 1H), 3.95 (dd, J = 11.5, 3.8 Hz, 1H),3.84-3.63 (m, 2H), 3.49 (ddd, J = 45.5, 14.7, 10.8 Hz, 3H), 3.23 (s,1H), 2.54 (s, 3H), 2.48 (s, 3H), 2.07 (s, 3H). 630.6 4.8 275

1H NMR (400 MHz, DMSO-d6) δ 8.88-8.73 (m, 2H), 8.65 (t, J = 8.9 Hz, 1H),7.63 (dd, J = 12.3, 5.2 Hz, 3H), 7.49 (s, 1H), 6.77 (t, J = 8.9 Hz, 1H),6.45 (dd, J = 11.7, 7.9 Hz, 2H), 4.76-4.58 (m, 1H), 4.31 (s, 1H), 4.10(s, 3H), 3.72 (ddd, J = 34.5, 14.4, 4.5 Hz, 1H), 3.44 (ddd, J = 29.6,14.4, 9.7 Hz, 1H), 2.58 (s, 3H), 1.76 (d, J = 10.8 Hz, 1H), 1.53 (t, J =15.8 Hz, 1H), 0.93 (t, J = 7.3 Hz, 3H). 671.2 4.8 276

1H NMR (400 MHz, DMSO-d6) δ 9.66-9.50 (m, 1H), 8.91-8.72 (m, 2H), 8.65(td, J = 8.4, 1.7 Hz, 1H), 8.39 (dd, J = 8.3, 1.3 Hz, 1H), 8.18 (d, J =8.5 Hz, 1H), 8.05 (ddd, J = 8.6, 6.9, 1.4 Hz, 1H), 7.95-7.80 (m, 1H),7.79-7.47 (m, 3H), 6.76 (t, J = 8.3 Hz, 1H), 6.44 (dd, J = 11.5, 7.1 Hz,2H), 4.75-4.59 (m, 1H), 4.30 (s, 1H), 3.83-3.60 (m, 1H), 3.44 (ddd, J =25.0, 14.3, 9.9 Hz, 1H), 1.90- 1.66 (m, 1H), 1.61-1.21 (m, 1H),0.97-0.79 (m, 3H). 677.2 4.9 277

1H NMR (400 MHz, DMSO-d6) δ 9.03-8.92 (m, 2H), 8.76 (dd, J = 8.6, 1.6Hz, 1H), 8.22 (s, 1H), 7.99 (s, 1H), 7.90 (d, J = 7.4 Hz, 1H), 7.80-7.69(m, 2H), 6.74 (d, J = 11.8 Hz, 2H), 4.97-4.84 (m, 1H), 4.80-4.70 (m,1H), 4.17 (d, J = 12.7 Hz, 1H), 3.96 (dd, J = 11.5, 3.8 Hz 1H), 3.81(dd, J = 14.3, 4.4 Hz, 1H), 3.73 (d, J = 12.8 Hz, 1H), 3.61-3.35 (m,3H), 3.23 (t, J = 12.5 Hz, 1H). 644.3 5.2 278

1H NMR (400 MHz, DMSO-d6) δ 8.85 (dd, J = 4.2, 1.6 Hz, 1H), 8.82 (d, J =8.0 Hz, 1H), 8.67 (dd, J = 8.7, 1.7 Hz, 1H), 8.17 (d, J = 1.6 Hz, 1H),7.92 (dd, J = 7.9, 1.7 Hz, 1H), 7.69-7.60 (m, 3H), 7.59 (d, J = 7.9 Hz,1H), 6.56 (d, J = 12.3 Hz, 2H), 4.71 (td, J = 8.8, 8.1, 4.3 Hz, 1H),3.77 (d, J = 18.6 Hz, 1H), 3.44 (s, 1H), 3.26 (t, J = 5.0 Hz, 4H), 1.52(dd, J = 9.7, 5.6 Hz, 6H). 574.8 82.2 279

1H NMR (400 MHz, DMSO-d6) δ 10.35 (d, J = 1.2 Hz, 1H), 8.84 (tt, J =3.2, 1.6 Hz, 2H), 8.50 (dd, J = 8.6, 1.7 Hz, 1H), 7.99 (s, 1H), 7.73-7.55 (m, 5H), 7.12 (t, J = 8.1 Hz, 2H), 3.30 (s, 1H). ; 1H NMR (400 MHz,DMSO-d6) δ 9.03 (d, J = 8.9 Hz, 1H), 8.85 (dd, J = 4.1, 1.5 Hz, 1H),8.61 (dd, J = 8.7, 1.7 Hz, 1H), 7.93 (d, J = 7.5 Hz, 1H), 7.74- 7.57 (m,4H), 7.43 (tt, J = 8.4, 6.4 Hz, 1H), 7.14-6.95 (m, 2H), 6.07 (d, J = 2.8Hz, 1H), 4.91 (dd, J = 8.9, 2.7 Hz, 1H). 535.0 82.4 280

1H NMR (400 MHz, DMSO-d6) δ 9.31 (d, J = 8.2 Hz, 1H), 8.84 (dd, J = 4.1,1.6 Hz, 1H), 8.64 (dd, J = 8.7, 1.7 Hz, 1H), 8.16 (dd, J = 1.6, 0.4 Hz,1H), 7.90 (dd, J = 7.9, 1.6 Hz, 1H), 7.69-7.54 (m, 4H), 7.30 (d, J = 8.9Hz, 2H), 6.96 (s, 1H), 4.85-4.71 (m, 1H), 3.77 (s, 1H), 3.39 (s, 1H).604.2 86.1 281

1H NMR (400 MHz, DMSO-d6) δ 8.99 (d, J = 7.9 Hz, 1H), 8.62 (t, J = 2.7Hz, 1H), 7.58 (s, 1H), 7.45 (t, J = 6.6 Hz, 1H), 7.12 (d, J = 7.2 Hz,1H), 6.77 (dd, J = 11.6, 4.2 Hz, 2H), 6.55 (d, J = 2.2 Hz, 1H),4.98-4.87 (m, 1H), 4.75-4.65 (m, 1H), 4.16 (d, J = 12.7 Hz, 1H),3.99-3.93 (m, 1H), 3.74 (d, J = 13.1 Hz, 2H), 3.67-3.50 (m, 1H), 3.48(d, J = 1.5 Hz, 3H), 3.46- 3.18 (m, 3H), 3.10 (d, J = 4.4 Hz, 6H), 2.53(s, 3H). 742.6 5.5 282

1H NMR (400 MHz, DMSO-d6) δ 8.84-8.80 (m, 2H), 8.62 (dd, J = 8.7, 1.6Hz, 1H), 7.66-7.49 (m, 8H), 7.45-7.35 (m, 3H), 6.54 (d, J = 11.3 Hz,2H), 5.70 (p, J = 8.3 Hz, 1H), 4.70 (ddd, J = 10.1, 8.0, 4.4 Hz, 1H),3.72 (dd, J = 14.4, 4.4 Hz, 1H), 3.39 (dd, J = 14.5, 10.3 Hz, 1H). 692.026.8 283

1H NMR (400 MHz, DMSO-d6) δ 8.90 (ddd, J = 4.8, 1.6, 0.7 Hz, 1H), 8.81(d, J = 8.0 Hz, 1H), 8.78 (dd, J = 4.2, 1.6 Hz, 1H), 8.64 (dd, J = 8.7,1.7 Hz, 1H), 8.33-8.29 (m, 1H), 7.70 (ddd, J = 8.0, 4.8, 0.9 Hz, 1H),7.64-7.59 (m, 3H), 6.84 (d, J = 9.2 Hz, 1H), 6.42 (d, J = 11.4 Hz, 2H),4.73-4.66 (m, 1H), 4.51 (td, J = 14.3, 6.9 Hz, 1H), 3.74 (dd, J = 14.3,4.4 Hz, 1H), 3.44 (dd, J = 14.4, 10.1 Hz, 1H), 1.27 (d, J = 6.7 Hz, 3H).613.1 5.7 284

1H NMR (400 MHz, DMSO-d6) δ 8.86-8.75 (m, 2H), 8.63 (dd, J = 8.7, 1.7Hz, 1H), 8.15 (dd, J = 1.6, 0.4 Hz, 1H), 7.90 (dd, J = 7.9, 1.7 Hz, 1H),7.67-7.53 (m, 4H), 7.25 (s, 1H), 6.27 (d, J = 11.5 Hz, 2H), 5.81 (t, J =55.6 Hz, 1H), 4.67 (s, 1H), 3.72 (s, 1H), 3.41 (s, 1H), 1.18-1.10 (m,2H), 0.85 (s, 2H). 597.2 45.9 285

1H NMR (400 MHz, DMSO-d6) δ 9.08 (d, J = 8.4 Hz, 1H), 8.84 (dd, J = 4.2,1.6 Hz, 1H), 8.76-8.61 (m, 1H), 8.17 (d, J = 1.6 Hz, 1H), 7.91 (s, 1H),7.72-7.58 (m, 3H), 7.55 (d, J = 7.9 Hz, 1H), 7.48 (d, J = 3.2 Hz, 1H),6.44 (d, J = 3.1 Hz, 1H), 4.87 (s, 1H), 3.77 (s, 3H), 3.74 (d, J = 4.2Hz, 1H), 3.48- 3.34 (m, 1H). 577.0 46.2 286

1H NMR (400 MHz, DMSO-d6) δ 9.18 (d, J = 8.1 Hz, 1H), 8.84 (dd, J = 4.2,1.6 Hz, 1H), 8.64 (dd, J = 8.6, 1.6 Hz, 1H), 8.16 (d, J = 1.6 Hz, 1H),7.90 (dd, J = 7.9, 1.6 Hz, 1H), 7.68-7.59 (m, 3H), 7.57 (d, J = 7.9 Hz,1H), 6.94 (d, J = 8.8 Hz, 2H), 4.80-4.69 (m, 1H), 3.80 (pd, J = 8.9,7.6, 3.0 Hz, 2H), 3.40 (s, 1H), 2.62 (d, J = 6.2 Hz, 2H), 1.02 (d, J =6.1 Hz, 3H). 550.2 47.3 287

1H NMR (400 MHz, DMSO-d6) δ 8.93 (dd, J = 11.1, 6.5 Hz, 2H), 8.80 (dd, J= 8.1, 4.4 Hz, 1H), 7.81 (ddd, J = 15.3, 8.5, 4.8 Hz, 1H), 7.72-7.63 (m,2H), 7.59 (t, J = 6.5 Hz, 1H), 6.76 (dd, J = 9.4, 4.1 Hz, 1H), 6.48-6.33(m, 2H), 4.72 (qd, J = 10.7, 4.5 Hz, 1H), 4.30 (d, J = 8.8 Hz, 1H), 3.70(dd, J = 14.6, 4.8 Hz, 1H), 3.57-3.32 (m, 4H), 2.75-2.62 (m, 6H), 1.82(d, J = 11.0 Hz, 3H), 1.75 (dd, J = 7.1, 3.5 Hz, 1H), 1.53 (ddd, J =13.7, 10.4, 7.1 Hz, 1H), 0.92 (t, J = 7.3 Hz, 3H). 646.3 5.7 288

1H NMR (400 MHz, DMSO-d6) δ 8.83-8.79 (m, 2H), 8.65 (dd, J = 8.7, 1.7Hz, 1H), 8.23-8.22 (m, 2H), 7.68-7.59 (m, 3H), 6.84 (d, J = 9.2 Hz, 1H),6.41 (d, J = 11.4 Hz, 2H), 4.73 (ddd, J = 10.1, 8.0, 4.5 Hz, 1H), 4.51(dq, J = 14.2, 6.9 Hz, 1H), 3.75 (dd, J = 14.6, 4.5 Hz, 1H), 3.44 (dd, J= 14.5, 10.2 Hz, 1H), 1.27 (d, J = 6.7 Hz, 3H). 637.1 5.8 289

1H NMR (400 MHz, DMSO-d6) δ 12.86 (s, 1H), 8.86-8.78 (m, 2H), 8.66 (dd,J = 8.7, 1.7 Hz, 1H), 8.20 (d, J = 8.2 Hz, 1H), 7.66-7.59 (m, 3H), 7.56(d, J = 8.2 Hz, 1H), 6.78 (d, J = 9.4 Hz, 1H), 6.45 (d, J = 11.5 Hz,2H), 4.69 (ddd, J = 9.8, 7.9, 4.5 Hz, 1H), 4.38-4.25 (m, 1H), 3.74 (dd,J = 14.3, 4.5 Hz, 1H), 3.44 (dd, J = 14.4, 9.9 Hz, 1H), 2.58 (s, 3H),1.76 (ddt, J = 13.1, 10.5, 5.3 Hz, 1H), 1.52 (ddq, J = 14.4, 10.4, 7.3Hz, 1H), 0.92 (t, J = 7.3 Hz, 3H). 641.8 6.5 290

1H NMR (400 MHz, DMSO-d6) δ 8.87 (dd, J = 14.3, 7.8 Hz, 1H), 8.72 (ddd,J = 8.7, 4.1, 1.8 Hz, 1H), 8.68-8.58 (m, 2H), 8.55 (dt, J = 8.4, 1.8 Hz,1H), 8.29 (d, J = 8.8 Hz, 1H), 8.01 (d, J = 8.8 Hz, 1H), 7.67-7.51 (m,3H), 6.76 (dd, J = 9.5, 5.2 Hz, 1H), 6.53-6.38 (m, 2H), 4.75 (t, J =11.1 Hz, 1H), 4.31 (s, 1H), 3.70 (d, J = 5.3 Hz, 1H), 1.77 (s, 1H), 1.53(q, J = 13.4, 10.2 Hz, 1H), 1.02-0.83 (m, 3H). 677.2 6.5 291

1H NMR (400 MHz, DMSO-d6) δ 9.03 (d, J = 8.1 Hz, 1H), 8.89 (d, J = 4.1Hz, 1H), 8.74 (d, J = 8.6 Hz, 1H), 8.15 (s, 1H), 7.85 (d, J = 27.1 Hz,2H), 7.74-7.67 (m, 2H), 6.77 (d, J = 12.0 Hz, 2H), 4.91 (d, J = 9.4 Hz,1H), 4.72 (m, 1H), 4.17 (d, J = 12.7 Hz, 1H), 3.95 (m, 1H), 3.76 (m,4H), 3.60-3.38 (m, 4H), 3.24 (t, J = 12.6 Hz, 1H), 2.62 (s, 3H). 631.26.9 292

1H NMR (400 MHz, DMSO-d6) δ 8.83 (dd, J = 4.2, 1.6 Hz, 1H), 8.76 (d, J =8.0 Hz, 1H), 8.65 (dd, J = 8.7, 1.7 Hz, 1H), 8.15 (d, J = 1.7 Hz, 1H),7.90 (dd, J = 7.9, 1.7 Hz, 1H), 7.69-7.58 (m, 3H), 7.57 (d, J = 7.9 Hz,1H), 6.50 (d, J = 12.8 Hz, 2H), 4.69 (d, J = 8.0 Hz, 1H), 3.90 (d, J =11.7 Hz, 1H), 3.84- 3.64 (m, 2H), 3.48 (t, J = 11.7 Hz, 2H), 3.38 (dtd,J = 11.4, 5.8, 3.0 Hz, 2H), 3.13 (td, J = 12.7, 3.7 Hz, 1H), 2.39-2.23(m, 1H), 0.94 (d, J = 6.6 Hz, 3H), 0.68 (d, J = 6.8 Hz, 3H). 620.4 26.9293

1H NMR (400 MHz, DMSO-d6) δ 9.29 (d, J = 8.2 Hz, 1H), 8.81 (dd, J = 4.2,1.6 Hz, 1H), 8.64 (dd, J = 8.7, 1.7 Hz, 1H), 8.22 (q, J = 1.6 Hz, 2H),7.75 (dtd, J = 9.1, 3.1, 1.6 Hz, 3H), 7.68-7.56 (m, 5H), 6.91- 6.81 (m,2H), 4.84-4.73 (m, 3H), 3.77 (dd, J = 14.5, 4.4 Hz, 1H), 3.41 (dd, J =14.6, 10.5 Hz, 1H). 680.2 6.9 294

1H NMR (400 MHz, DMSO-d6) δ 9.39 (d, J = 4.9 Hz, 1H), 9.35 (d, J = 8.8Hz, 1H), 8.95 (d, J = 5.2 Hz, 1H), 8.90 (s, 1H), 8.79 (d, J = 8.3 Hz,1H), 8.14 (dd, J = 8.6, 5.0 Hz, 1H), 7.96 (d, J = 7.8 Hz, 1H), 7.60 (d,J = 5.2 Hz, 1H), 6.77 (d, J = 9.4 Hz, 1H), 6.41 (d, J = 11.6 Hz, 2H),4.78 (ddd, J = 10.3, 8.3, 4.5 Hz, 1H), 4.29 (d, J = 8.9 Hz, 1H), 3.89(dd, J = 14.4, 4.5 Hz, 1H), 3.55 (dd, J = 14.4, 10.4 Hz, 1H), 2.71 (s,3H), 1.77 (ddd, J = 13.7, 7.3, 3.3 Hz, 1H), 1.52 (ddd, J = 13.8, 10.4,7.1 Hz, 1H), 0.91 (t, J = 7.3 Hz, 3H). 575.3 7.4 295

1H NMR (400 MHz, DMSO-d6) δ 8.84 (dd, J = 4.2, 1.5 Hz, 1H), 8.78 (d, J =8.1 Hz, 1H), 8.67 (dd, J = 8.7, 1.7 Hz, 1H), 7.65 (d, J = 9.3 Hz, 3H),6.76 (d, J = 9.4 Hz, 1H), 6.44 (d, J = 11.6 Hz, 2H), 4.70 (td, J = 9.2,8.1, 4.5 Hz, 1H), 4.31 (d, J = 3.2 Hz, 1H), 3.74 (dd, J = 14.3, 4.6 Hz,1H), 3.43 (dd, J = 14.4, 10.0 Hz, 1H), 2.54 (s, 3H), 2.48 (s, 3H), 2.07(s, 3H), 1.77 (ddd, J = 14.0, 7.4, 3.4 Hz, 1H), 1.52 (ddt, J = 17.6,14.2, 7.3 Hz, 1H), 0.92 (t, J = 7.3 Hz, 3H). 602.2 7.4 296

1H NMR (400 MHz, DMSO-d6) δ 8.89 (d, J = 4.1 Hz, 1H), 8.79 (t, J = 10.0Hz, 1H), 8.64 (d, J = 9.2 Hz, 1H), 7.87 (d, J = 10.9 Hz, 1H), 7.66-7.57(m, 2H), 6.89 (d, J = 10.7 Hz, 1H), 6.76 (d, J = 9.2 Hz, 1H), 6.44 (d, J= 11.9 Hz, 2H), 4.66 (s, 1H), 4.30 (d, J = 8.8 Hz, 1H), 3.75 (d, J =14.2 Hz, 1H), 3.51 (s, 3H), 3.45-3.30 (m, 1H), 1.76 (ddd, J = 13.8, 7.3,3.3 Hz, 1H), 1.58-1.45 (m, 1H), 0.92 (t, J = 7.3 Hz, 3H). 657.2 7.7 297

1H NMR (400 MHz, DMSO-d6) δ 11.52 (d, J = 2.2 Hz, 1H), 9.03 (d, J = 8.6Hz, 1H), 8.90 (d, J = 4.3 Hz, 1H), 7.95-7.71 (m, 2H), 7.64 (s, 1H),7.36-7.17 (m, 6H), 6.78 (d, J = 6.0 Hz, 2H), 6.17 (dd, J = 2.2, 1.0 Hz,1H), 4.89 (ddd, J = 10.7, 8.5, 4.0 Hz, 1H), 4.55 (s, 2H), 4.07 (s, 2H),3.79 (dd, J = 14.5, 4.0 Hz, 1H), 3.61 (s, 3H), 3.59 (q, J = 7.0 Hz, 2H),3.57 (s, 3H), 3.51-3.37 (m, 1H), 1.22 (t, J = 7.0 Hz, 3H). 712.5 7.9 298

1H NMR (400 MHz, DMSO-d6) δ 8.93 (dd, J = 7.9, 4.5 Hz, 1H), 8.83 (d, J =4.2 Hz, 1H), 8.71-8.64 (m, 1H), 7.68-7.61 (m, 1H), 7.58 (t, J = 6.8 Hz,1H), 7.46 (dd, J = 7.4, 3.7 Hz, 1H), 6.55 (s, 1H), 6.26 (dd, J = 9.9,5.2 Hz, 2H), 4.99- 4.87 (m, 1H), 4.75-4.65 (m, 1H), 4.12-4.03 (m, 1H),3.80-3.65 (m, 2H), 3.49 (d, J = 2.3 Hz, 3H), 2.69-2.56 (m, 1H), 2.53 (s,3H), 2.44-2.34 (m, 1H). 669.3 7.9 299

1H NMR (400 MHz, DMSO-d6) δ 13.11 (s, 1H), 9.40 (t, J = 8.4 Hz, 2H),9.03-8.92 (m, 2H), 8.90 (s, 1H), 8.17 (dd, J = 8.7, 5.1 Hz, 1H), 7.98(d, J = 7.8 Hz, 1H), 6.72 (d, J = 11.8 Hz, 2H), 4.93-4.77 (m, 2H), 4.15(d, J = 12.7 Hz, 1H), 3.93 (td, J = 15.3, 13.6, 4.2 Hz, 2H), 3.74-3.68(m, 1H), 3.61- 3.48 (m, 2H), 3.40 (d, J = 12.7 Hz, 1H), 3.28-3.05 (m,5H), 2.20 (p, J = 7.7 Hz, 2H). 628.3 8.2 300

1H NMR (400 MHz, DMSO-d6) δ 8.93 (dd, J = 4.2, 1.6 Hz, 1H), 8.83 (d, J =8.3 Hz, 1H), 8.76 (dd, J = 8.7, 1.7 Hz, 1H), 8.54 (d, J = 5.8 Hz, 1H),7.93 (d, J = 5.8 Hz, 1H), 7.84 (d, J = 7.3 Hz, 1H), 7.76 (dd, J = 8.3,4.3 Hz, 2H), 6.78 (d, J = 9.4 Hz, 1H), 6.44 (d, J = 11.5 Hz, 2H), 4.73(td, J = 9.2, 8.3, 4.2 Hz, 1H), 4.31 (d, J = 9.7 Hz, 1H), 3.83 (dd, J =14.2, 4.3 Hz, 1H), 3.45 (dd, J = 14.2, 10.4 Hz, 1H), 2.60 (s, 3H), 2.29(s, 6H), 1.78 (ddd, J = 13.7, 7.3, 3.3 Hz, 1H), 1.53 (ddd, J = 13.8,10.4, 7.2 Hz, 1H), 0.92 (t, J = 7.3 Hz, 3H). 616.1 8.4 301

1H NMR (400 MHz, DMSO-d6) δ 9.24-9.17 (m, 1H), 9.18-9.09 (m, 1H), 8.95(s, 1H), 8.94 (s, 1H), 8.51-8.40 (m, 1H), 8.02-7.92 (m, 1H), 7.87-7.80(m, 1H), 6.74 (d, J = 11.7 Hz, 2H), 4.95-4.85 (m, 1H), 4.82-4.72 (m,1H), 4.15 (d, J = 12.6 Hz, 1H), 3.95 (dd, J = 11.6, 3.6 Hz, 1H), 3.85(dd, J = 14.4, 4.2 Hz, 1H), 3.72 (d, J = 12.6 Hz, 1H), 3.59-3.46 (m,2H), 3.44- 3.38 (m, 1H), 3.27-3.15 (m, 1H), 2.65 (s, 3H). 620.2 9.4 302

1H NMR (400 MHz, DMSO-d6) δ 8.82 (d, J = 7.7 Hz, 1H), 8.80- 8.75 (m,1H), 8.61 (d, J = 8.6 Hz, 1H), 7.60 (td, J = 8.7, 7.7, 4.9 Hz, 3H), 7.49(d, J = 7.3 Hz, 1H), 7.37 (d, J = 10.1 Hz, 1H), 7.03 (s, 1H), 6.77 (d, J= 9.3 Hz, 1H), 6.46 (d, J = 11.6 Hz, 2H), 4.67 (d, J = 11.0 Hz, 1H),4.31 (s, 1H), 3.67 (s, 4H), 2.97 (s, 6H), 1.53 (s, 1H), 0.93 (t, J = 7.3Hz, 3H). 750.9 9.4 303

1H NMR (400 MHz, DMSO-d6) δ 9.41 (d, J = 0.8 Hz, 1H), 9.33- 9.23 (m,1H), 8.83-8.68 (m, 2H), 8.34-8.18 (m, 2H), 8.02 (ddd, J = 8.4, 7.0, 1.3Hz, 1H), 7.86 (ddd, J = 8.1, 6.9, 1.1 Hz, 1H), 7.81-7.58 (m, 3H),7.47-7.33 (m, 3H), 4.92- 4.81 (m, 1H), 3.79 (dd, J = 14.5, 4.3 Hz, 1H),3.45 (dd, J = 14.5, 10.4 Hz, 1H). 594.1 9.4 304

1H NMR (400 MHz, DMSO-d6) δ 9.27 (d, J = 8.6 Hz, 1H), 8.89 (d, J = 2.8Hz, 1H), 8.46 (dd, J = 10.5, 2.8 Hz, 1H), 8.25-8.18 (m, 1H), 7.78 (d, J= 7.4 Hz, 1H), 7.62 (d, J = 7.3 Hz, 1H), 7.47-7.28 (m, 2H), 4.85 (s,1H), 3.73-3.65 (m, 1H), 3.41 (d, J = 11.0 Hz, 1H). 576.0 9.6 305

1H NMR (400 MHz, DMSO-d6) δ 13.01 (s, 1H), 8.88 (dd, J = 4.2, 1.5 Hz,1H), 8.85-8.70 (m, 3H), 8.61 (s, 1H), 8.01 (s, 1H), 7.90 (d, J = 7.3 Hz,1H), 7.72 (dd, J = 8.3, 4.1 Hz, 2H), 6.77 (d, J = 9.4 Hz, 1H), 6.43 (d,J = 11.7 Hz, 2H), 4.76 (td, J = 9.4, 8.4, 4.2 Hz, 1H), 4.30 (s, 2H),3.82 (dd, J = 14.3, 4.3 Hz, 1H), 3.45 (dd, J = 14.4, 10.3 Hz, 1H),2.62-2.56 (m, 1H), 1.77 (ddd, J = 14.0, 7.4, 3.2 Hz, 1H), 1.52 (ddd, J =13.6, 10.3, 7.0 Hz, 1H), 1.08 (d, J = 6.8 Hz, 6H), 0.92 (t, J = 7.3 Hz,3H). 601.1 10.2 306

1H NMR (400 MHz, DMSO-d6) δ 9.35 (d, J = 8.1 Hz, 1H), 8.88 (s, 1H), 8.77(dd, J = 4.4, 1.5 Hz, 1H), 8.68 (d, J = 4.9 Hz, 1H), 7.89- 7.68 (m, 3H),7.51 (tt, J = 8.4, 6.5 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.15 (dd, J =8.4, 7.6 Hz, 2H), 4.83 (td, J = 9.3, 4.3 Hz, 1H), 4.58 (t, J = 5.9 Hz,2H), 3.85 (dd, J = 14.5, 4.4 Hz, 1H), 3.57-3.36 (m, 3H). 525.9 11.2 307

1H NMR (400 MHz, DMSO-d6) δ 13.05 (s, 1H), 8.90 (dd, J = 4.2, 1.6 Hz,1H), 8.86 (d, J = 8.2 Hz, 1H), 8.80-8.70 (m, 2H), 7.98 (d, J = 6.0 Hz,1H), 7.92 (d, J = 7.3 Hz, 1H), 7.79-7.71 (m, 2H), 6.80 (d, J = 9.4 Hz,1H), 6.44 (d, J = 11.5 Hz, 2H), 4.79-4.69 (m, 1H), 4.39-4.23 (m, 1H),3.83 (dd, J = 14.2, 4.3 Hz, 1H), 3.45 (dd, J = 14.3, 10.3 Hz, 1H), 2.63(s, 3H), 2.04 (s, 3H), 1.85-1.70 (m, 1H), 1.61-1.44 (m, 1H), 0.92 (t, J= 7.3 Hz, 3H). 587.5 11.4 308

1H NMR (400 MHz, DMSO-d6) δ 9.29 (dd, J = 25.4, 8.3 Hz, 1H), 8.87 (p, J= 4.1, 1.9 Hz, 1H), 8.72 (d, J = 8.6 Hz, 1H), 7.74-7.61 (m, 2H),7.52-7.33 (m, 4H), 6.59 (dt, J = 4.7, 1.2 Hz, 1H), 4.83 (dddd, J = 36.2,10.6, 8.3, 3.9 Hz, 1H), 4.10- 3.98 (m, 2H), 3.81-3.68 (m, 1H), 3.50-3.33(m, 1H), 3.33- 3.15 (m, 2H), 2.27-2.13 (m, 2H). 589.8 11.9 309

1H NMR (400 MHz, DMSO-d6) δ 9.51-9.46 (m, 1H), 9.44 (d, J = 8.8 Hz, 1H),9.05 (d, J = 7.7 Hz, 1H), 8.82 (s, 1H), 8.79 (d, J = 8.4 Hz, 1H), 8.21(dd, J = 8.7, 5.2 Hz, 1H), 8.00 (d, J = 7.8 Hz, 1H), 6.78 (d, J = 9.4Hz, 1H), 6.41 (d, J = 11.6 Hz, 2H), 4.80 (ddd, J = 10.3, 8.3, 4.5 Hz,1H), 4.28 (d, J = 8.8 Hz, 1H), 3.90 (dd, J = 14.3, 4.6 Hz, 1H), 3.56(dd, J = 14.4, 10.3 Hz, 1H), 2.70 (s, 3H), 2.41 (s, 3H), 1.76 (dtd, J =14.7, 7.4, 3.2 Hz, 1H), 1.52 (dtd, J = 13.8, 7.2, 3.1 Hz, 1H), 0.91 (t,J = 7.3 Hz, 3H). 589.6 11.9 310

1H NMR (400 MHz, DMSO-d6) δ 12.86 (s, 1H), 8.81 (d, J = 8.0 Hz, 1H),8.78 (dd, J = 4.2, 1.5 Hz, 1H), 8.73 (d, J = 1.9 Hz, 1H), 8.64 (dt, J =8.7, 1.7 Hz, 1H), 8.14 (d, J = 2.0 Hz, 1H), 7.67-7.55 (m, 3H), 6.77 (d,J = 9.4 Hz, 1H), 6.44 (d, J = 11.6 Hz, 2H), 4.74-4.65 (m, 1H), 4.31 (d,J = 9.7 Hz, 1H), 3.73 (dd, J = 14.5, 4.5 Hz, 1H), 3.43 (dd, J = 14.5,10.0 Hz, 1H), 2.50 (s, 3H), 1.77 (ddd, J = 13.9, 7.2, 3.3 Hz, 1H), 1.52(ddd, J = 13.7, 10.4, 7.1 Hz, 1H), 0.92 (t, J = 7.3 Hz, 3H). 641.8 12.3311

1H NMR (400 MHz, DMSO-d6) δ 13.03 (s, 1H), 9.26 (d, J = 28.9 Hz, 2H),8.86 (s, 1H), 8.79 (d, J = 8.2 Hz, 1H), 8.73 (s, 1H), 8.05 (s, 1H), 7.89(d, J = 7.6 Hz, 1H), 6.77 (d, J = 9.4 Hz, 1H), 6.42 (d, J = 11.7 Hz,2H), 4.75 (d, J = 12.0 Hz, 1H), 4.29 (d, J = 9.4 Hz, 1H), 3.86 (d, J =14.2 Hz, 1H), 3.57-3.48 (m, 1H), 3.09 (q, J = 7.6 Hz, 4H), 2.19 (p, J =7.6 Hz, 2H), 1.76 (ddd, J = 10.6, 7.4, 3.6 Hz, 1H), 1.52 (ddd, J = 13.7,10.3, 7.1 Hz, 1H), 0.91 (t, J = 7.3 Hz, 3H). 600.2 12.3 312

1H NMR (400 MHz, DMSO-d6) δ 9.19 (d, 1H), 9.12 (d, J = 7.7 Hz, 1H), 8.96(d, J = 8.3 Hz, 1H), 8.92 (s, 1H), 8.47 (s, 1H), 7.97 (dd, J = 8.5, 4.7Hz, 1H), 7.85 (d, J = 7.6 Hz, 1H), 6.74 (d, J = 11.9 Hz, 2H), 4.95-4.84(m, 1H), 4.83-4.73 (m, 1H), 4.54 (s, 1H), 4.16 (d, J = 12.7 Hz, 1H),4.00-3.67 (m, 4H), 3.60-3.46 (m, 4H), 3.40 (d, J = 12.4 Hz, 1H), 3.33(t, 2H), 3.28- 3.18 (m, 1H), 3.05 (s, 3H). 657.2 12.5 313

1H NMR (400 MHz, DMSO-d6) δ 8.95 (dd, J = 4.2, 1.4 Hz, 1H), 8.82 (d, J =8.3 Hz, 1H), 8.75 (dd, J = 8.8, 1.6 Hz, 1H), 8.22 (s, 1H), 7.98 (s, 1H),7.90 (d, J = 7.4 Hz, 1H), 7.81-7.68 (m, 2H), 6.78 (d, J = 9.4 Hz, 1H),6.43 (d, J = 11.6 Hz, 2H), 4.72 (ddd, J = 10.1, 8.1, 4.4 Hz, 1H), 4.30(d, J = 8.4 Hz, 2H), 3.80 (dd, J = 14.2, 4.4 Hz, 1H), 3.44 (dd, J =14.2, 10.3 Hz, 1H), 1.85-1.69 (m, 1H), 1.62-1.43 (m, 1H), 0.92 (t, J =7.3 Hz, 3H). 616.3 13.3 314

1H NMR (400 MHz, DMSO-d6) δ 9.29 (d, J = 8.4 Hz, 1H), 8.90 (d, J = 5.0,0.7 Hz, 1H), 8.86 (dd, J = 4.2, 1.6 Hz, 1H), 8.70 (dd, J = 8.7, 1.7 Hz,1H), 7.97 (d, J = 5.1 Hz, 1H), 7.76-7.64 (m, 3H), 7.46- 7.35 (m, 3H),4.92-4.83 (m, 1H), 3.79 (dd, J = 14.5, 4.2 Hz, 1H), 3.44 (dd, J = 14.6,10.6 Hz, 1H). 569.4 13.4 315

1H NMR (400 MHz, DMSO-d6) δ 8.96 (d, J = 4.2 Hz, 1H), 8.82 (d, J = 8.2Hz, 1H), 8.76 (d, J = 8.6 Hz, 1H), 8.31 (d, J = 5.3 Hz, 1H), 8.10 (s,1H), 7.92 (d, J = 7.7 Hz, 1H), 7.81-7.67 (m, 2H), 6.78 (d, J = 9.4 Hz,1H), 6.44 (d, J = 11.6 Hz, 2H), 4.80-4.67 (m, 1H), 4.30 (s, 1H), 3.81(dd, J = 14.1, 4.4 Hz, 1H), 3.45 (dd, J = 14.2, 10.3 Hz, 1H), 1.78 (ddd,J = 13.7, 7.3, 3.3 Hz, 1H), 1.54 (dt, J = 10.2, 6.8 Hz, 1H), 0.92 (t, J= 7.3 Hz, 3H). 602.3 13.6 316

1H NMR (400 MHz, DMSO-d6) δ 11.26 (s, 1H), 9.23 (d, J = 8.1 Hz, 1H),8.93 (dd, J = 4.2, 1.5 Hz, 1H), 8.73 (s, 1H), 8.67-8.54 (m, 2H), 7.71(dd, J = 8.6, 4.2 Hz, 1H), 7.57- 7.38 (m, 2H), 7.12 (dd, J = 8.5, 7.6Hz, 2H), 4.68 (td, J = 9.0, 4.6 Hz, 1H), 3.66 (dd, J = 14.3, 4.6 Hz,1H), 3.34 (dd, J = 14.4, 9.8 Hz, 1H). 545.1 13.7 317

1H NMR (400 MHz, DMSO-d6) δ 11.67 (s, 1H), 9.11 (d, J = 8.4 Hz, 1H),8.84 (dd, J = 4.2, 1.6 Hz, 1H), 8.67 (dd, J = 8.7, 1.7 Hz, 1H), 8.17 (d,J = 1.6 Hz, 1H), 7.92 (d, J = 7.9 Hz, 1H), 7.80-7.39 (m, 5H), 6.50 (dd,J = 3.1, 1.9 Hz, 1H), 4.87 (s, 1H), 3.76 (dd, J = 14.4, 4.1 Hz, 1H),3.41 (dd, J = 14.5, 10.7 Hz, 1H). 565.0 13.8 318

1H NMR (400 MHz, DMSO-d6) δ 9.42-9.22 (m, 1H), 8.78 (dt, J = 3.8, 1.8Hz, 1H), 8.68 (t, J = 8.2 Hz, 1H), 8.48 (d, J = 8.4 Hz, 1H), 8.20 (d, J= 8.6 Hz, 1H), 8.05 (ddd, J = 8.5, 6.9, 1.3 Hz, 1H), 7.91 (t, J = 7.7Hz, 1H), 7.79- 7.58 (m, 3H), 7.56-7.45 (m, 1H), 7.14 (q, J = 7.9 Hz,2H), 4.91- 4.66 (m, 1H), 3.78 (ddd, J = 28.6, 14.5, 4.7 Hz, 1H), 3.47(ddd, J = 24.2, 14.5, 9.8 Hz, 1H), 2.99 (d, J = 2.0 Hz, 3H). 566.2 14.3319

1H NMR (400 MHz, DMSO-d6) δ 13.02 (s, 1H), 9.46 (d, J = 4.4 Hz, 1H),9.16 (br, 1H), 8.78-8.62 (m, 2H), 8.24 (d, J = 8.6 Hz, 1H), 7.85 (s,1H), 7.68-7.56 (m, 3H), 7.50 (dd, J = 8.5, 1.5 Hz, 1H), 7.46- 7.35 (m,3H), 4.75 (m, 1H), 3.85- 3.58 (m, 1H), 3.43 (t, J = 11.9 Hz, 1H),2.37-2.19 (m, 1H), 1.24- 1.10 (m, 2H), 0.99-0.79 (m, 2H). 626.0 14.4 320

1H NMR (400 MHz, DMSO-d6) δ 8.85 (d, J = 4.2 Hz, 1H), 8.78 (d, J = 8.1Hz, 1H), 8.69 (d, J = 8.6 Hz, 1H), 7.71-7.45 (m, 3H), 6.76 (d, J = 9.3Hz, 1H), 6.44 (d, J = 11.6 Hz, 2H), 4.71 (td, J = 9.0, 4.4 Hz, 1H), 4.30(d, J = 9.9 Hz, 1H), 3.76 (dd, J = 14.3, 4.5 Hz, 1H), 3.43 (dd, J =14.3, 10.1 Hz, 1H), 2.61 (s, 3H), 2.54 (s, 3H), 1.85 (s, 3H), 1.77 (ddd,J = 13.8, 7.2, 3.2 Hz, 1H), 1.53 (ddt, J = 17.6, 14.4, 7.3 Hz, 1H), 0.92(t, J = 7.3 Hz, 3H). 602.2 15.3 321

1H NMR (400 MHz, DMSO-d6) δ 8.85-8.79 (m, 2H), 8.66-8.61 (m, 1H), 7.90(d, J = 8.2 Hz, 1H), 7.65-7.60 (m, 2H), 7.36 (d, J = 8.2 Hz, 1H), 6.78(d, J = 9.4 Hz, 1H), 6.45 (d, J = 11.5 Hz, 2H), 4.73-4.61 (m, 1H),4.38-4.23 (m, 1H), 3.78-3.69 (m, 1H), 3.48- 3.38 (m, 1H), 2.50 (s, 3H),1.84- 1.69 (m, 1H), 1.61-1.45 (m, 1H), 0.92 (t, J = 7.3 Hz, 3H). 607.215.8 322

1H NMR (400 MHz, DMSO-d6) δ 9.36 (d, J = 8.2 Hz, 1H), 8.91- 8.79 (m,2H), 8.64 (d, J = 8.8 Hz, 1H), 8.16 (d, J = 1.6 Hz, 1H), 7.90 (d, J =8.0 Hz, 1H), 7.69-7.59 (m, 2H), 7.57 (d, J = 8.3 Hz, 3H), 4.80 (s, 1H),4.30 (d, J = 39.4 Hz, 1H), 3.38 (s, 2H), 2.65 (s, 1H), 2.31 (s, 1H).639.3 16.2 323

1H NMR (400 MHz, DMSO-d6) δ 9.17 (d, J = 8.5 Hz, 1H), 8.84 (dd, J = 4.2,1.5 Hz, 1H), 8.67 (dd, J = 8.7, 1.7 Hz, 1H), 8.41 (s, 1H), 8.17 (d, J =1.6 Hz, 1H), 7.92 (d, J = 7.8 Hz, 1H), 7.72-7.58 (m, 4H), 7.55 (d, J =7.9 Hz, 1H), 4.87 (s, 1H), 3.77 (dd, J = 14.4, 4.2 Hz, 1H), 3.49-3.33(m, 1H). 564.0 17.1 324

1H NMR (400 MHz, DMSO-d6) δ 8.85-8.72 (m, 2H), 8.60 (dd, J = 8.7, 1.6Hz, 1H), 8.15 (dd, J = 1.7, 0.4 Hz, 1H), 7.89 (dd, J = 7.9, 1.7 Hz, 1H),7.66-7.50 (m, 4H), 7.49- 7.41 (m, 2H), 7.41-7.24 (m, 4H), 6.43-6.11 (m,3H), 5.16- 5.04 (m, 1H), 4.64 (s, 1H), 3.70 (s, 1H), 3.37 (s, 1H). 647.118.7 325

1H NMR (400 MHz, DMSO-d6) δ 8.86-8.80 (m, 2H), 8.67-8.62 (m, 1H), 8.47(d, J = 4.9 Hz, 1H), 7.63-7.60 (m, 2H), 7.49 (d, J = 5.0 Hz, 1H), 6.78(d, J = 9.4 Hz, 1H), 6.45 (d, J = 11.6 Hz, 2H), 4.74-4.60 (m, 1H),4.39-4.25 (m, 1H), 3.74 (dd, J = 14.5, 4.5 Hz, 1H), 3.47-3.37 (m, 1H),2.45 (s, 3H), 1.85-1.70 (m, 1H), 1.52 (dt, J = 17.7, 7.2 Hz, 1H), 0.92(t, J = 7.3 Hz, 3H). 607.1 18.8 326

1H NMR (400 MHz, DMSO-d6) δ 8.85-8.73 (m, 2H), 8.61 (d, J = 8.7 Hz, 1H),8.15 (dd, J = 1.7, 0.4 Hz, 1H), 7.89 (dd, J = 7.9, 1.6 Hz, 1H),7.66-7.52 (m, 4H), 7.49- 7.42 (m, 2H), 7.41-7.26 (m, 4H), 6.44-6.10 (m,3H), 5.10 (q, J = 12.3 Hz, 1H), 4.64 (s, 1H), 3.70 (s, 1H), 3.37 (s,1H). 647.2 19.1 327

1H NMR (400 MHz, DMSO-d6) δ 8.84-8.79 (m, 2H), 8.62 (dd, J = 8.7, 1.7Hz, 1H), 8.47-8.43 (m, 1H), 7.88-7.85 (m, 1H), 7.64- 7.59 (m, 2H), 6.78(d, J = 9.4 Hz, 1H), 6.45 (d, J = 11.5 Hz, 2H), 4.73-4.63 (m, 1H),4.37-4.24 (m, 1H), 3.77-3.67 (m, 1H), 3.48- 3.36 (m, 1H), 2.41 (s, 3H),1.83- 1.69 (m, 1H), 1.59-1.45 (m, 1H), 0.92 (t, J = 7.3 Hz, 3H), . 607.219.3 328

1H NMR (400 MHz, DMSO-d6) δ 8.88 (d, J = 8.1 Hz, 1H), 8.85 (dd, J = 4.1,1.6 Hz, 1H), 8.66 (dd, J = 8.7, 1.7 Hz, 1H), 8.17 (d, J = 1.7 Hz, 1H),7.91 (dd, J = 7.9, 1.7 Hz, 1H), 7.68-7.60 (m, 3H), 7.58 (d, J = 7.9 Hz,1H), 6.62 (d, J = 11.9 Hz, 2H), 4.72 (td, J = 9.1, 8.7, 4.3 Hz, 1H),3.91-3.83 (m, 1H), 3.71 (d, J = 12.3 Hz, 1H), 3.65-3.49 (m, 3H), 3.43(s, 2H), 2.70 (td, J = 12.1, 3.7 Hz, 1H), 2.38 (dd, J = 12.4, 10.4 Hz,1H), 1.13 (d, J = 6.2 Hz, 3H). 591.8 19.4 329

1H NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H), 9.13 (d, J = 8.1 Hz, 1H),8.86 (d, J = 4.6 Hz, 1H), 7.91- 7.45 (m, 3H), 7.37-7.16 (m, 2H), 6.75(d, J = 3.0 Hz, 2H), 4.76 (td, J = 8.8, 8.1, 4.5 Hz, 1H), 4.53 (s, 2H),3.79-3.73 (m, 1H), 3.57 (dd, J = 8.2, 7.4 Hz, 8H), 3.49- 3.38 (m, 1H),2.05 (s, 3H), 1.21 (t, J = 7.0 Hz, 3H). 608.4 20.1 330

1H NMR (400 MHz, DMSO-d6) δ 9.29 (t, J = 9.2 Hz, 1H), 8.83- 8.74 (m,2H), 8.65 (dd, J = 8.7, 1.6 Hz, 1H), 7.68-7.58 (m, 4H), 7.48- 7.34 (m,3H), 4.90-4.74 (m, 1H), 3.74 (dt, J = 14.8 Hz, 1H), 3.42 (dd, J = 14.5,10.2 Hz, 1H), 1.68 (ddd, J = 13.2, 8.4, 4.9 Hz, 1H), 1.07-0.95 (m, 2H),0.87- 0.78 (m, 2H). 599.7 21.0 331

1H NMR (400 MHz, DMSO-d6) δ 8.90-8.74 (m, 2H), 8.61 (dd, J = 8.7, 1.7Hz, 1H), 8.15 (dd, J = 1.6, 0.4 Hz, 1H), 7.89 (dd, J = 7.9, 1.7 Hz, 1H),7.69-7.43 (m, 6H), 7.31- 7.21 (m, 2H), 6.52 (d, J = 11.4 Hz, 2H), 5.73(p, J = 8.3 Hz, 1H), 4.66 (s, 1H), 3.71 (s, 1H), 3.37 (s, 1H). 683.122.9 332

1H NMR (400 MHz, DMSO-d6) δ 8.86-8.76 (m, 2H), 8.63 (dd, J = 8.8, 1.6Hz, 1H), 8.15 (d, J = 1.7 Hz, 1H), 7.89 (dd, J = 7.9, 1.7 Hz, 1H), 7.61(s, 2H), 7.57 (d, J = 7.9 Hz, 1H), 7.02 (t, J = 6.9 Hz, 1H), 6.42 (d, J= 11.4 Hz, 2H), 4.78- 4.59 (m, 1H), 4.08-3.95 (m, 2H), 3.72 (s, 1H),3.41 (s, 1H). 589.1 23.7 333

1H NMR (400 MHz, DMSO-d6) δ 8.86-8.76 (m, 2H), 8.63 (dd, J = 8.7, 1.7Hz, 1H), 8.16 (dd, J = 1.6, 0.4 Hz, 1H), 7.90 (dd, J = 7.9, 1.7 Hz, 1H),7.68-7.49 (m, 4H), 6.70 (d, J = 9.7 Hz, 1H), 6.47 (d, J = 11.7 Hz, 2H),4.68 (s, 1H), 4.42 (d, J = 8.1 Hz, 2H), 3.73 (s, 1H), 3.41 (s, 1H), 2.61(q, J = 8.2 Hz, 1H), 1.98-1.71 (m, 6H). 643.2 24.1 334

1H NMR (400 MHz, DMSO-d6) δ 8.86-8.79 (m, 2H), 8.62 (dd, J = 8.7, 1.7Hz, 1H), 8.15 (dd, J = 1.6, 0.4 Hz, 1H), 7.89 (dd, J = 7.9, 1.7 Hz, 1H),7.66-7.37 (m, 8H), 7.28- 7.18 (m, 1H), 6.53 (d, J = 11.4 Hz, 2H), 5.76(p, J = 8.1 Hz, 1H), 4.65 (d, J = 10.7 Hz, 1H), 3.77- 3.65 (m, 1H), 3.36(s, 1H). 683.2 24.2 335

1H NMR (400 MHz, DMSO-d6) δ 12.96 (s, 1H), 11.47 (s, 1H), 9.00 (d, J =8.0 Hz, 1H), 8.85 (s, 1H), 7.63 (d, J = 40.1 Hz, 2H), 7.40- 7.12 (m,5H), 6.94 (d, J = 9.8 Hz, 1H), 6.85-6.69 (m, 2H), 6.22 (d, J = 2.0 Hz,1H), 4.76 (d, J = 11.0 Hz, 1H), 4.53 (s, 2H), 4.04 (s, 2H), 3.75 (d, J =13.8 Hz, 1H), 3.57 (dd, J = 9.5, 6.9 Hz, 1H), 1.21 (t, J = 7.0 Hz, 3H).680.3 25.1 336

1H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 9.27 (d, J = 8.3 Hz, 1H), 9.01(dd, J = 4.2, 1.5 Hz, 1H), 8.81 (d, J = 5.8 Hz, 1H), 8.75- 8.68 (m, 1H),8.61 (s, 1H), 8.22 (s, 1H), 7.97 (d, J = 5.9 Hz, 1H), 7.78 (dd, J = 8.6,4.2 Hz, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.47-7.30 (m, 4H), 4.81 (td, J =8.9, 4.9 Hz, 1H), 3.39 (dd, J = 14.5, 9.7 Hz, 2H). 532.0 26.1 337

1H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 9.16 (d, J = 8.2 Hz, 1H),8.84 (dd, J = 4.2, 1.6 Hz, 1H), 8.64 (dd, J = 8.7, 1.7 Hz, 1H), 8.15(dd, J = 1.7, 0.4 Hz, 1H), 7.92- 7.85 (m, 2H), 7.81 (t, J = 7.6 Hz, 1H),7.77-7.70 (m, 2H), 7.67- 7.59 (m, 3H), 7.57 (dd, J = 7.9, 0.4 Hz, 1H),7.38 (d, J = 9.7 Hz, 2H), 4.76 (s, 1H), 3.8 (br, 1H). 679.1 26.2 338

1H NMR (400 MHz, DMSO-d6) δ 8.86-8.74 (m, 2H), 8.63 (dd, J = 8.7, 1.7Hz, 1H), 8.15 (dd, J = 1.6, 0.4 Hz, 1H), 7.90 (dd, J = 7.9, 1.6 Hz, 1H),7.67-7.59 (m, 3H), 7.57 (dd, J = 7.9, 0.4 Hz, 1H), 6.73 (d, J = 10.2 Hz,1H), 6.50 (d, J = 11.8 Hz, 2H), 4.65-4.72 (m, 1H), 4.44- 4.32 (m, 1H),3.84 (td, J = 12.2, 4.2 Hz, 2H), 3.72 (s, 1H), 3.40 (s, 1H), 3.33-3.21(m, 2H), 1.97 (d, J = 10.8 Hz, 1H), 1.55 (d, J = 13.2 Hz, 2H), 1.48-1.32(m, 2H). 788.1 26.5 339

1H NMR (400 MHz, DMSO-d6) δ 8.92 (dd, J = 7.9, 4.3 Hz, 1H), 8.84 (dd, J= 4.3, 1.4 Hz, 1H), 8.68 (d, J = 8.0 Hz, 1H), 7.66 (dt, J = 8.7, 4.4 Hz,1H), 7.60 (t, J = 7.7 Hz, 1H), 7.46 (dd, J = 7.3, 2.1 Hz, 1H), 6.63 (dd,J = 12.0, 4.7 Hz, 2H), 6.56 (d, J = 1.8 Hz, 1H), 4.69 (ddd, J = 13.2,8.8, 4.9 Hz, 2H), 3.80-3.63 (m, 1H), 3.49 (d, J = 2.2 Hz, 3H), 3.48-3.34(m, 1H), 3.34-3.21 (m, 1H), 3.21-3.07 (m, 1H), 2.54 (s, 3H), 1.90 (ddd,J = 14.2, 10.5, 7.1 Hz, 1H), 1.76 (ddt, J = 11.2, 7.3, 4.0 Hz, 1H),1.61-1.34 (m, 2H), 0.86 (dt, J = 10.9, 7.3 Hz, 6H). 713.2 0.6 340

1H NMR (400 MHz, DMSO-d6) δ 8.93 (d, J = 4.4 Hz, 1H), 8.89- 8.71 (m,2H), 7.75 (s, 1H), 7.62 (td, J = 18.5, 17.8, 7.5 Hz, 2H), 6.93-6.77 (m,1H), 6.38 (dd, J = 11.3, 2.7 Hz, 2H), 4.76-4.61 (m, 1H), 4.49 (q, J =7.5 Hz, 1H), 3.87- 3.74 (m, 1H), 3.66 (dd, J = 14.5, 4.8 Hz, 1H),3.54-3.48 (m, 1H), 3.45 (d, J = 1.7 Hz, 3H), 3.34 (dd, J = 14.4, 10.6Hz, 1H), 3.22 (d, J = 2.5 Hz, 3H), 1.93 (d, J = 9.9 Hz, 3H), 1.25 (d, J= 6.7 Hz, 3H). 620.2 0.6 341

1H NMR (400 MHz, DMSO-d6) δ 12.97 (s, 1H), 9.06 (s, 1H), 8.96 (s, 1H),8.84 (d, J = 8.0 Hz, 1H), 7.89 (s, 1H), 7.78-7.60 (m, 2H), 6.79 (d, J =9.4 Hz, 1H), 6.51- 6.38 (m, 3H), 4.69 (s, 1H), 4.31 (d, J = 9.6 Hz, 1H),3.74 (d, J = 11.7 Hz, 1H), 3.67 (d, J = 4.4 Hz, 3H), 3.45 (s, 4H), 1.78(dt, J = 10.8, 3.7 Hz, 1H), 1.53 (ddd, J = 13.8, 10.5, 7.1 Hz, 1H), 0.92(t, J = 7.3 Hz, 3H). 633.2 0.6 342

1H NMR (400 MHz, DMSO-d6) δ 8.95-8.83 (m, 2H), 8.80 (d, J = 8.0 Hz, 1H),7.84-7.70 (m, 1H), 7.70-7.61 (m, 1H), 7.61-7.50 (m, 1H), 6.94 (dd, J =9.5, 4.6 Hz, 1H), 6.40 (dd, J = 11.4, 3.6 Hz, 2H), 6.21 (d, J = 2.7 Hz,1H), 4.77- 4.65 (m, 1H), 3.99-3.87 (m, 1H), 3.84-3.64 (m, 1H), 3.53-3.32 (m, 4H), 2.42 (s, 3H), 1.80- 1.70 (m, 3H), 1.11-0.98 (m, 1H),0.68-0.58 (m, 1H), 0.55-0.44 (m, 2H), 0.35-0.27 (m, 1H). 629.2 0.7 343

1H NMR (400 MHz, DMSO-d6) δ 8.87 (d, J = 4.3 Hz, 1H), 8.85- 8.79 (m,1H), 8.75 (d, J = 8.7 Hz, 1H), 7.74-7.65 (m, 1H), 7.63 (dd, J = 7.4, 3.1Hz, 1H), 7.54 (d, J = 7.4 Hz, 1H), 6.77 (dd, J = 9.3, 3.8 Hz, 1H),6.52-6.42 (m, 3H), 4.68 (qd, J = 8.4, 4.5 Hz, 1H), 4.38- 4.19 (m, 1H),3.74-3.66 (m, 1H), 3.53-3.37 (m, 4H), 2.46 (s, 3H), 1.77 (ddd, J = 13.6,7.2, 3.2 Hz, 1H), 1.61-1.45 (m, 1H), 0.93 (t, J = 7.3 Hz, 4H). 639.2 0.7344

1H NMR (400 MHz, DMSO-d6) δ 8.76-8.64 (m, 2H), 7.54-7.42 (m, 2H), 7.32(d, J = 7.3 Hz, 1H), 6.72 (d, J = 12.1 Hz, 2H), 6.51 (s, 1H), 5.00-4.85(m, 1H), 4.36 (s, 1H), 3.73-3.55 (m, 2H), 3.48 (s, 3H), 3.29 (s, 3H),3.02 (t, J = 12.1 Hz, 1H), 1.95 (d, J = 14.7 Hz, 1H), 1.87-1.67 (m, 2H),1.67-1.43 (m, 3H), 0.91-0.77 (m, 2H). 697.2 0.8 345

1H NMR (400 MHz, DMSO-d6) δ 8.89 (s, 2H), 8.79 (d, J = 8.0 Hz, 1H), 7.78(d, J = 11.8 Hz, 1H), 7.65 (dd, J = 11.1, 7.4 Hz, 1H), 7.54 (t, J = 6.8Hz, 1H), 6.75 (dd, J = 9.5, 4.3 Hz, 1H), 6.41 (dd, J = 11.3, 3.2 Hz,2H), 6.20 (d, J = 2.9 Hz, 1H), 4.69 (dt, J = 13.3, 9.3 Hz, 1H), 4.29 (d,J = 9.7 Hz, 1H), 3.74 (ddd, J = 46.6, 14.4, 4.6 Hz, 1H), 3.55-3.30 (m,4H), 2.41 (s, 3H), 1.74 (d, J = 11.1 Hz, 3H), 1.50 (ddd, J = 13.9, 10.5,7.1 Hz, 1H), 0.90 (t, J = 7.3 Hz, 3H). 617.2 0.8 346

1H NMR (400 MHz, DMSO-d6) δ 9.00 (dd, J = 12.1, 7.5 Hz, 1H), 8.82 (d, J= 4.2 Hz, 1H), 8.57 (d, J = 8.7 Hz, 1H), 7.68-7.56 (m, 2H), 7.44 (dd, J= 7.2, 2.9 Hz, 1H), 6.81- 6.73 (m, 1H), 6.55 (s, 1H), 6.45 (dd, J =11.5, 5.6 Hz, 2H), 5.76 (dd, J = 11.1, 6.1 Hz, 2H), 4.74 (dd, J = 13.7,7.1 Hz, 1H), 4.34 (d, J = 2.1 Hz, 1H), 3.70-3.61 (m, 1H), 3.51 (s, 3H),3.43 (d, J = 10.0 Hz, 1H), 2.53 (s, 3H), 1.76 (d, J = 8.0 Hz, 1H), 1.53(dq, J = 13.7, 7.1 Hz, 1H), 1.16 (d, J = 1.9 Hz, 9H), 0.92 (t, J = 7.3Hz, 3H). 785.2 NA 347

1H NMR (400 MHz, DMSO-d6) δ 8.98 (t, J = 6.8 Hz, 1H), 8.82 (d, J = 4.2Hz, 1H), 8.62 (d, J = 8.6 Hz, 1H), 7.63 (dd, J = 8.5, 4.3 Hz, 1H), 7.56(d, J = 7.4 Hz, 1H), 7.45 (d, J = 7.3 Hz, 1H), 6.79 (dd, J = 9.5, 4.4Hz, 1H), 6.55 (s, 1H), 6.47 (dd, J = 11.4, 3.9 Hz, 2H), 4.86 (d, J = 9.4Hz, 1H), 4.69 (d, J = 13.6 Hz, 1H), 4.35-4.28 (m, 1H), 3.82- 3.60 (m,3H), 3.57-3.36 (m, 6H), 2.53 (s, 3H), 1.85-1.65 (m, 3H), 1.53 (ddd, J =17.2, 8.9, 5.3 Hz, 2H), 1.39 (t, J = 9.7 Hz, 1H), 0.93 (t, J = 7.3 Hz,3H). 755.2 NA 348

1H NMR (400 MHz, DMSO-d6) δ 9.00 (t, J = 7.1 Hz, 1H), 8.83 (d, J = 4.2Hz, 1H), 8.63 (s, 1H), 7.62 (dd, J = 8.9, 4.6 Hz, 1H), 7.55 (t, J = 7.0Hz, 1H), 7.44 (t, J = 6.6 Hz, 1H), 6.78 (d, J = 9.8 Hz, 1H), 6.55 (s,1H), 6.45 (d, J = 11.9 Hz, 2H), 5.06-4.96 (m, 2H), 4.74 (d, J = 7.9 Hz,1H), 4.32 (d, J = 9.2 Hz, 1H), 3.67 (dt, J = 12.6, 5.8 Hz, 1H), 3.49 (s,4H), 2.53 (s, 3H), 2.14 (d, J = 3.7 Hz, 3H), 1.76 (d, J = 10.4 Hz, 1H),1.53 (d, J = 9.1 Hz, 1H), 0.93 (t, J = 7.3 Hz, 3H). 783.2 NA 349

1H NMR (400 MHz, DMSO-d6) δ 9.06-8.93 (m, 1H), 8.81 (d, J = 4.0 Hz, 1H),8.56 (t, J = 10.6 Hz, 1H), 7.65-7.51 (m, 2H), 7.44 (d, J = 6.4 Hz, 1H),6.85-6.69 (m, 2H), 6.54 (s, 1H), 6.50-6.35 (m, 2H), 4.79-4.65 (m, 1H),4.32 (s, 1H), 3.63 (d, J = 13.8 Hz, 1H), 3.49 (s, 4H), 2.53 (s, 3H),2.08- 1.97 (m, 2H), 1.77 (s, 1H), 1.55 (d, J = 15.3 Hz, 1H), 1.44 (t, J= 5.0 Hz, 1H), 1.29 (d, J = 5.4 Hz, 1H), 0.93 (q, J = 6.5, 5.8 Hz, 2H),−0.00 (d, J = 1.6 Hz, 3H). 757.2 NA 350

1H NMR (400 MHz, DMSO-d6) δ 9.81 (d, J = 41.6 Hz, 1H), 9.08 (t, J = 8.0Hz, 1H), 8.83 (t, J = 5.3 Hz, 1H), 8.58 (dd, J = 37.4, 9.3 Hz, 1H),7.66-7.56 (m, 1H), 7.46 (dd, J = 9.5, 6.6 Hz, 1H), 6.85 (d, J = 9.6 Hz,1H), 6.58 (d, J = 8.8 Hz, 1H), 6.49 (dd, J = 11.5, 2.6 Hz, 2H),4.86-4.76 (m, 1H), 4.47- 4.37 (m, 1H), 4.38-4.29 (m, 1H), 4.24-4.14 (m,1H), 3.99-3.90 (m, 1H), 3.73 (dd, J = 15.6, 4.8 Hz, 1H), 3.70-3.60 (m,2H), 3.59- 3.52 (m, 1H), 3.50 (s, 2H), 3.43- 3.34 (m, 1H), 3.34-3.26 (m,2H), 3.22-3.08 (m, 2H), 2.54 (d, J = 2.3 Hz, 3H), 1.83-1.72 (m, 1H),1.57-1.46 (m, 1H), 0.96- 0.90 (m, 3H). 784. 2 NA 351

1H NMR (400 MHz, DMSO-d6) δ 9.01-8.91 (m, 1H), 8.79 (d, J = 4.3 Hz, 1H),8.57 (d, J = 8.5 Hz, 1H), 7.60 (dd, J = 8.5, 4.2 Hz, 1H), 7.51 (t, J =7.9 Hz, 1H), 7.42 (d, J = 7.6 Hz, 1H), 6.78 (dd, J = 9.4, 6.0 Hz, 1H),6.53 (d, J = 0.9 Hz, 1H), 6.44 (dd, J = 11.5, 5.7 Hz, 2H), 4.72 (dd, J =10.4, 7.2 Hz, 1H), 4.30 (s, 1H), 3.72-3.29 (m, 6H), 2.51 (s, 3H),1.80-1.71 (m, 1H), 1.58-1.45 (m, 1H), 0.91 (t, J = 7.3 Hz, 3H). 685.2 NA352

1H NMR (400 MHz, DMSO-d6) δ 8.88-8.77 (m, 2H), 8.66 (d, J = 8.7 Hz, 1H),7.70-7.56 (m, 2H), 7.45 (t, J = 7.2 Hz, 1H), 6.71- 6.60 (m, 2H), 6.55(d, J = 3.3 Hz, 1H), 4.89-4.69 (m, 2H), 4.14 (d, J = 12.6 Hz, 1H),3.99-3.89 (m, 1H), 3.81-3.73 (m, 2H), 3.55- 3.42 (m, 4H), 3.41-3.30 (m,1H), 3.30-3.17 (m, 1H), 2.53 (s, 3H). 698.13 NA 353

1H NMR (400 MHz, DMSO-d6) δ 8.78 (s, 1H), 8.64 (d, J = 8.5 Hz, 1H), 7.54(s, 1H), 7.52-7.35 (m, 2H), 7.00 (t, J = 10.6 Hz, 1H), 6.50 (d, J = 30.6Hz, 3H), 5.31 (d, J = 6.2 Hz, 1H), 5.08 (s, 1H), 4.67 (s, 1H), 4.57 (s,1H), 4.35 (s, 1H), 3.49 (s, 3H), 2.53 (s, 3H), 1.78 (s, 1H), 1.53 (d, J= 15.1 Hz, 1H), 1.25 (d, J = 6.4 Hz, 1H), 0.93 (d, J = 6.2 Hz, 3H).683.2 NA 354

1H NMR (400 MHz, DMSO-d6) δ 8.86 (m, 2H), 7.75 (s, 1H), 7.67 (s, 1H),7.60 (d, J = 7.5 Hz, 1H), 7.03 (d, J = 9.4 Hz, 1H), 6.54 (d, J = 12.4Hz, 2H), 5.36 (d, J = 4.4 Hz, 1H), 5.03 (m, 2H), 3.79 (d, J = 6.2 Hz,1H), 3.53 (s, 3H), 2.42 (s, 3H), 2.34 (s, 3H), 1.79 (m, 1H), 1.55 (s,1H), 0.94 (t, J = 7.4 Hz, 3H) 630.2 NA

Examples 355-406 in Table 3 were prepared by processes described herein.

TABLE 3 α4β7 M/Z EC₅₀ Example Structure 1H-NMR [M + H]+ (nM) 355

1H NMR (400 MHz, DMSO-d6) δ 9.05 (s, 1H), 9.00 (d, J = 7.7 Hz, 1H), 8.85(d, J = 4.1 Hz, 1H), 8.66 (dd, J = 8.7, 1.5 Hz, 1H), 8.60 (d, J = 4.9Hz, 1H), 7.91 (dd, J = 4.9, 3.2 Hz, 1H), 7.77 (d, J = 7.5 Hz, 1H),7.72-7.58 (m, 2H), 6.79-6.61 (m, 2H), 4.83 (td, J = 9.2, 8.4, 4.4 Hz,2H), 4.15 (d, J = 12.6 Hz, 1H), 3.93 (d, J = 3.7 Hz, 1H), 3.68 (s, 3H),3.66 (d, J = 2.3 Hz, 4H), 3.53 (dp, J = 14.9, 5.8, 5.2 Hz, 2H),3.40-3.18 (m, 2H), 2.05 (s, 3H). 695.2 NA 356

1H NMR (400 MHz, DMSO-d6) δ 9.05 (s, 1H), 8.92-8.77 (m, 2H), 8.68 (d, J= 8.6 Hz, 1H), 8.60 (d, J = 5.0 Hz, 1H), 7.91 (t, J = 4.3 Hz, 1H), 7.76(d, J = 7.6 Hz, 1H), 7.67 (dd, J = 8.3, 4.5 Hz, 2H), 6.74-6.58 (m, 2H),5.00-4.59 (m, 2H), 4.14 (d, J = 12.6 Hz, 1H), 3.99-3.91 (m, 1H), 3.66(d, J = 2.4 Hz, 4H), 3.59-3.40 (m, 1H), 3.31 (dd, J = 35.1, 12.3 Hz,3H), 2.03 (s, 3H). 681.2 0.05 357

1H NMR (400 MHz, DMSO-d6) δ 9.15-9.00 (m, 2H), 8.85 (d, J = 3.9 Hz, 1H),8.67-8.57 (m, 2H), 7.91 (ddd, J = 5.0, 3.1, 0.8 Hz, 1H), 7.76 (d, J =7.5 Hz, 1H), 7.73-7.61 (m, 2H), 5.83 (s, 2H), 4.85 (d, J = 9.2 Hz, 2H),4.14 (d, J = 12.6 Hz, 1H), 4.06-3.88 (m, 1H), 3.84-3.68 (m, 2H), 3.65(d, J = 2.2 Hz, 3H), 3.53 (dt, J = 14.8, 9.7 Hz, 2H), 3.36 (d, J = 12.3Hz, 1H), 3.26 (d, J = 12.1 Hz, 1H), 2.03 (s, 3H), 1.18 (s, 9H). 795.3 NA358

1H NMR (400 MHz, Chloroform- d) δ 9.28 (dt, J = 4.8, 1.6 Hz, 1H), 9.20(ddd, J = 8.7, 4.6, 1.5 Hz, 1H), 8.90 (d, J = 2.2 Hz, 1H), 8.62 (dd, J =5.0, 1.6 Hz, 1H), 8.04 (dd, J = 24.7, 5.0 Hz, 1H), 7.83 (dd, J = 8.6,4.7 Hz, 1H), 7.75 (d, J = 1.2 Hz, 2H), 7.46 (d, J = 7.0 Hz, 1H), 6.49(d, J = 2.4 Hz, 1H), 6.43-6.27 (m, 1H), 5.18 (q, J = 7.6 Hz, 1H), 4.97(dd, J = 12.8, 6.4 Hz, 1H), 4.53 (td, J = 9.2, 7.8, 4.6 Hz, 1H), 4.31(d, J = 12.4 Hz, 1H), 4.16 (ddt, J = 19.3, 8.0, 3.3 Hz, 1H), 4.10-3.90(m, 2H), 3.82 (dd, J = 12.5, 2.2 Hz, 1H), 3.72 (d, J = 9.4 Hz, 3H), 3.60(ddt, J = 32.1, 17.2, 8.3 Hz, 3H), 3.28 (d, J = 12.0 Hz, 1H), 3.22-3.09(m, 1H), 3.03 (s, 4H), 2.32 (s, 3H), 1.49-1.10 (m, 9H), 1.02 (d, J =780.3 NA 7.6 Hz, 2H). 359

1H NMR (400 MHz, DMSO-d6) δ 9.22 (d, J = 7.1 Hz, 1H), 9.05 (s, 1H), 8.86(dd, J = 4.1, 1.5 Hz, 1H), 8.76 (dd, J = 8.7, 1.5 Hz, 1H), 8.61 (d, J =4.9 Hz, 1H), 7.93 (d, J = 4.9 Hz, 1H), 7.81 (d, J = 7.5 Hz, 1H), 7.73(d, J = 7.6 Hz, 1H), 7.68 (dd, J = 8.6, 4.2 Hz, 1H), 7.44 (td, J = 8.4,7.9, 1.4 Hz, 2H), 7.28 (t, J = 7.4 Hz, 1H), 7.06 (ddd, J = 8.5, 2.3, 1.1Hz, 2H), 6.73 (d, J = 13.4 Hz, 1H), 6.70-6.64 (m, 1H), 5.05 (q, J = 7.3Hz, 1H), 4.93-4.78 (m, 1H), 4.15 (d, J = 12.5 Hz, 1H), 3.95 (dd, J =11.4, 3.6 Hz, 1H), 3.86 (dd, J = 14.6, 5.6 Hz, 1H), 3.72 (dd, J = 14.3,9.9 Hz, 2H), 3.67 (s, 3H), 3.60-3.49 (m, 1H), 3.37 (d, J = 12.4 Hz, 1H),3.26 (t, J = 12.1 Hz, 1H), 2.10 (d, J = 1.7 Hz, 3H). 757.2 NA 360

1H NMR (400 MHz, DMSO-d6) δ 9.04 (s, 1H), 8.99 (d, J = 7.7 Hz, 1H), 8.84(dd, J = 4.2, 1.4 Hz, 1H), 8.64 (dd, J = 8.7, 1.6 Hz, 1H), 8.60 (d, J =4.9 Hz, 1H), 7.91 (dd, J = 5.0, 2.2 Hz, 1H), 7.75 (d, J = 7.5 Hz, 1H),7.66 (dt, J = 8.6, 2.5 Hz, 2H), 6.76-6.63 (m, 2H), 4.82 (td, J = 14.4,12.1, 5.3 Hz, 2H), 4.20-4.04 (m, 3H), 3.95 (dd, J = 11.5, 3.6 Hz, 1H),3.80-3.66 (m, 2H), 3.65 (d, J = 1.6 Hz, 3H), 3.60-3.46 (m, 2H), 3.36 (d,J = 13.7 Hz, 1H), 3.31- 3.18 (m, 1H), 2.07 (s, 3H), 1.16 (td, J = 7.1,1.1 Hz, 3H). 709.2 NA 361

1H NMR (400 MHz, DMSO-d6) δ 9.05 (d, J = 5.5 Hz, 2H), 8.90- 8.81 (m,1H), 8.70-8.57 (m, 2H), 7.91 (d, J = 5.1 Hz, 1H), 7.76 (d, J = 7.6 Hz,1H), 7.67 (d, J = 7.9 Hz, 2H), 6.74-6.64 (m, 2H), 4.86 (s, 2H),4.35-4.06 (m, 3H), 3.95 (d, J = 11.0 Hz, 1H), 3.74 (d, J = 13.2 Hz, 6H),3.53 (q, J = 14.3, 13.3 Hz, 2H), 3.42- 3.13 (m, 2H), 2.03 (d, J = 20.9Hz, 3H), 1.53 (d, J = 5.4 Hz, 1H), 1.38 (d, J = 5.4 Hz, 2H), 1.23 (t, J= 7.1 Hz, 3H). 797.2 NA 362

1H NMR (400 MHz, DMSO-d6) δ 9.03 (d, J = 13.5 Hz, 2H), 8.85 (d, J = 4.3Hz, 1H), 8.65 (d, J = 8.7 Hz, 1H), 8.60 (d, J = 5.0 Hz, 1H), 7.96-7.88(m, 1H), 7.77 (d, J = 7.7 Hz, 1H), 7.72-7.61 (m, 2H), 6.81-6.59 (m, 2H),4.86 (d, J = 11.5 Hz, 2H), 4.21- 4.05 (m, 2H), 3.95 (dd, J = 11.7, 3.9Hz, 1H), 3.75 (dd, J = 15.2, 9.4 Hz, 3H), 3.66 (s, 4H), 3.36 (q, J =13.6 Hz, 1H), 3.27 (d, J = 11.9 Hz, 1H), 2.41-2.22 (m, 1H), 2.07 (d, J =6.2 Hz, 2H), 1.87 (ddt, J = 33.9, 14.4, 7.2 Hz, 2H), 1.76-1.36 (m, 1H).765.3 NA 363

1H NMR (400 MHz, DMSO-d6) δ 9.04 (s, 1H), 8.98 (d, J = 7.6 Hz, 1H), 8.83(dd, J = 4.1, 1.5 Hz, 1H), 8.68-8.56 (m, 2H), 7.91 (dt, J = 4.9, 1.0 Hz,1H), 7.75 (d, J = 7.6 Hz, 1H), 7.71-7.60 (m, 2H), 6.76-6.59 (m, 2H),4.89- 4.72 (m, 2H), 4.14 (dt, J = 9.3, 3.7 Hz, 2H), 3.95 (dd, J = 11.1,3.6 Hz, 1H), 3.80-3.62 (m, 5H), 3.52 (q, J = 14.4, 13.6 Hz, 2H), 3.36(d, J = 12.2 Hz, 1H), 3.22 (s, 1H), 2.04 (s, 3H), 0.75-0.52 (m, 4H).721.3 NA 364

1H NMR (400 MHz, DMSO-d6) δ 9.04 (d, J = 8.2 Hz, 2H), 8.87 (d, J = 4.1Hz, 1H), 8.64-8.57 (m, 2H), 7.91 (t, J = 4.8 Hz, 1H), 7.77 (d, 1H),7.71-7.59 (m, 3H), 7.56 (s, 1H), 6.74-6.65 (m, 2H), 4.90-4.76 (m, 2H),4.52- 4.42 (m, 1H), 4.41-4.28 (m, 3H), 4.15 (d, J = 12.6 Hz, 1H), 3.94(d, J = 3.5 Hz, 1H), 3.73 (d, J = 12.7 Hz, 1H), 3.69-3.60 (m, 4H),3.59-3.47 (m, 2H), 3.34 (d, 1H), 3.25 (t, 1H), 2.53 (s, 3H), 2.03 (s,3H). 789.3 NA 365

1H NMR (400 MHz, DMSO-d6) δ 9.04 (d, J = 2.1 Hz, 1H), 8.99 (d, J = 7.8Hz, 1H), 8.89-8.79 (m, 1H), 8.67 (d, J = 8.6 Hz, 1H), 8.60 (d, J = 5.0Hz, 1H), 7.91 (dt, J = 4.9, 2.4 Hz, 1H), 7.77 (dd, J = 7.5, 2.1 Hz, 1H),7.71-7.63 (m, 2H), 6.76-6.61 (m, 2H), 4.84 (d, J = 9.4 Hz, 2H), 4.14 (d,J = 12.6 Hz, 1H), 4.05 (q, J = 6.7 Hz, 2H), 3.95 (d, J = 11.3 Hz, 1H),3.73 (dd, J = 14.0, 4.4 Hz, 2H), 3.65 (d, J = 2.3 Hz, 3H), 3.54 (t, J =8.7 Hz, 2H), 3.36 (d, J = 12.4 Hz, 1H), 3.25 (t, J = 12.6 Hz, 1H), 2.05(s, 3H), 1.58 (h, J = 7.0 Hz, 2H), 0.88 (td, J = 7.4, 2.1 Hz, 3H). 723.3NA 366

1H NMR (400 MHz, DMSO-d6) δ 9.05 (s, 1H), 8.97 (d, J = 7.7 Hz, 1H), 8.84(d, J = 4.1 Hz, 1H), 8.65 (d, J = 8.7 Hz, 1H), 8.60 (d, J = 5.0 Hz, 1H),7.91 (d, J = 5.0 Hz, 1H), 7.76 (d, J = 7.5 Hz, 1H), 7.71-7.62 (m, 2H),6.71 (d, J = 13.1 Hz, 1H), 6.68-6.63 (m, 1H), 4.97-4.90 (m, 1H), 4.84(dd, J = 29.2, 20.4 Hz, 2H), 4.15 (d, J = 12.7 Hz, 1H), 3.95 (d, J =11.3 Hz, 1H), 3.73 (d, J = 13.7 Hz, 2H), 3.66 (s, 3H), 3.53 (q, J =13.5, 11.7 Hz, 2H), 3.36 (d, J = 12.3 Hz, 1H), 3.27 (d, J = 12.5 Hz,1H), 2.08 (d, J = 6.7 Hz, 3H), 1.22 (d, J = 6.2 Hz, 3H), 1.13 (d, J =6.3 Hz, 3H). 723.3 NA 367

1H NMR (400 MHz, DMSO-d6) δ 9.15-9.00 (m, 2H), 8.85 (d, J = 3.9 Hz, 1H),8.67-8.57 (m, 2H), 7.91 (ddd, J = 5.0, 3.1, 0.8 Hz, 1H), 7.76 (d, J =7.5 Hz, 1H), 7.73-7.61 (m, 2H), 5.83 (s, 2H), 4.85 (d, J = 9.2 Hz, 2H),4.14 (d, J = 12.6 Hz, 1H), 4.06-3.88 (m, 1H), 3.84-3.68 (m, 2H), 3.65(d, J = 2.2 Hz, 3H), 3.53 (dt, J = 14.8, 9.7 Hz, 2H), 3.36 (d, J = 12.3Hz, 1H), 3.26 (d, J = 12.1 Hz, 1H), 2.03 (s, 3H), 1.18 (s, 9H). 795.3 NA368

1H NMR (400 MHz, DMSO-d6) δ 9.02 (d, J = 18.4 Hz, 2H), 8.85 (d, J = 4.1Hz, 1H), 8.63 (dd, J = 22.3, 7.3 Hz, 2H), 7.92 (d, J = 4.9 Hz, 1H), 7.77(d, J = 7.6 Hz, 1H), 7.68 (t, J = 6.5 Hz, 2H), 6.82 (dq, J = 27.7, 5.5Hz, 1H), 6.75-6.63 (m, 2H), 4.84 (d, J = 10.7 Hz, 2H), 4.15 (d, J = 12.7Hz, 1H), 3.95 (d, J = 11.4 Hz, 1H), 3.81-3.61 (m, 5H), 3.53 (q, J =13.5, 12.8 Hz, 2H), 3.36 (d, J = 12.5 Hz, 1H), 3.26 (d, J = 12.5 Hz,1H), 2.15-1.96 (m, 6H), 1.42 (dd, J = 53.9, 5.5 Hz, 3H). 767.2 NA 369

1H NMR (400 MHz, DMSO-d6) δ 9.19 (d, J = 7.3 Hz, 1H), 9.05 (s, 1H), 8.86(d, J = 4.1 Hz, 1H), 8.75 (d, J = 8.6 Hz, 1H), 8.61 (d, J = 5.0 Hz, 1H),7.92 (d, J = 5.0 Hz, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.73 (d, J = 7.7 Hz,1H), 7.68 (dd, J = 8.7, 4.2 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 6.73 (d,J = 13.7 Hz, 1H), 6.67 (s, 1H), 6.56- 6.47 (m, 2H) 5.00 (s, 1H) 4.90-4.79 (m, 1H), 4.59 (t, J = 8.7 Hz, 2H), 4.15 (d, J = 12.7 Hz, 1H),3.99-3.91 (m, 1H), 3.85 (dd, J = 14.8, 5.2 Hz, 1H), 3.72 (t, J = 799.2NA 11.9 Hz, 2H), 3.66 (s, 3H), 3.54 (dd, J = 13.2, 9.8 Hz, 1H), 3.36 (d,J = 12.3 Hz, 1H), 3.27 (d, J = 12.0 Hz, 1H), 3.17 (t, J = 8.7 Hz, 2H),2.08 (d, J = 7.3 Hz, 3H). 370

1H NMR (400 MHz, DMSO-d6) δ 9.20 (d, J = 7.0 Hz, 1H), 9.05 (s, 1H), 8.86(d, J = 4.1 Hz, 1H), 8.74 (d, J = 8.5 Hz, 1H), 8.61 (d, J = 5.0 Hz, 1H),7.93 (d, J = 5.0 Hz, 1H), 7.80 (d, J = 7.5 Hz, 1H), 7.74-7.64 (m, 2H),6.85 (s, 1H), 6.79-6.64 (m, 4H), 4.99 (s, 1H), 4.85 (d, J = 9.7 Hz, 1H),4.54 (t, J = 8.7 Hz, 2H), 4.15 (d, J = 12.7 Hz, 1H), 3.96 (d, J = 11.5Hz, 2H), 3.81 (dd, J = 14.7, 6.2 Hz, 1H), 3.77-3.69 (m, 1H), 3.67 (s,3H), 3.55 (t, J = 11.3 Hz, 1H), 3.40-3.33 (m, 1H), 3.27 (d, J = 799.2 NA12.5 Hz, 1H), 3.19 (t, J = 8.8 Hz, 2H), 2.12 (d, J = 6.0 Hz, 3H). 371

1H NMR (400 MHz, DMSO-d6) δ 9.05 (s, 1H), 8.99 (d, J = 7.7 Hz, 1H), 8.85(d, J = 4.2 Hz, 1H), 8.60 (d, J = 5.0 Hz, 1H), 8.52 (d, J = 8.6 Hz, 1H),7.91 (t, J = 4.4 Hz, 1H), 7.75 (d, J = 7.5 Hz, 1H), 7.64 (dt, J = 16.5,5.8 Hz, 2H), 7.30 (d, J = 4.5 Hz, 5H), 7.23 (dt, J = 8.8, 4.9 Hz, 1H),6.76-6.60 (m, 2H), 4.84 (d, J = 8.8 Hz, 1H), 4.75 (d, J = 11.5 Hz, 1H),4.31 (m, 1H), 4.15 (d, J = 12.6 Hz, 1H), 3.95 (d, J = 9.8 Hz, 1H),3.79-3.69 (m, 2H), 3.56 (dt, J = 20.4, 9.0 Hz, 2H), 3.48-3.31 785.2 NA(m, 2H), 3.31-3.18 (m, 1H), 2.90 (t, J = 6.9 Hz, 2H), 2.05 (s, 3H). 372

1H NMR (400 MHz, DMSO-d6) δ 9.82 (s, 1H), 9.10-9.04 (m, 2H), 8.86 (d, J= 4.2 Hz, 1H), 8.66 (d, J = 8.6 Hz, 1H), 8.61 (d, J = 5.0 Hz, 1H), 7.92(d, J = 5.1 Hz, 1H), 7.79 (d, J = 7.5 Hz, 1H), 7.67 (dt, J = 7.9, 3.9Hz, 2H), 6.78-6.64 (m, 2H), 4.96-4.81 (m, 2H), 4.43 (s, 1H), 4.38-4.26(m, 1H), 4.16 (d, J = 12.6 Hz, 1H), 3.96 (d, J = 11.8 Hz, 3H), 3.74 (d,J = 12.6 Hz, 2H), 3.65-3.51 (m, 4H), 3.37 (d, J = 12.0 Hz, 4H), 3.27 (d,J = 13.6 Hz, 2H), 3.10 (d, J = 43.0 Hz, 2H), 2.10 (d, J = 794.3 NA 2.4Hz, 3H). 373

1H NMR (400 MHz, DMSO-d6) δ 9.04 (s, 1H), 8.95 (d, J = 7.7 Hz, 1H), 8.84(d, J = 4.1 Hz, 1H), 8.65 (d, J = 8.8 Hz, 1H), 8.60 (d, J = 4.8 Hz, 1H),7.91 (d, J = 4.8 Hz, 1H), 7.76 (d, J = 7.5 Hz, 1H), 7.67 (d, J = 6.7 Hz,2H), 6.71 (d, J = 13.1 Hz, 1H), 6.66 (s, 1H), 5.16-5.10 (m, 1H),4.88-4.75 (m, 2H), 4.15 (d, J = 12.8 Hz, 1H), 3.95 (d, J = 12.5 Hz, 1H),3.76-3.67 (m, 2H), 3.65 (s, 3H), 3.58-3.46 (m, 2H), 3.36 (d, J = 12.1Hz, 1H), 3.27 (d, J = 11.5 Hz, 1H), 2.04 (s, 2H), 1.90- 1.75 (m, 2H),1.72-1.50 (m, 6H). 749.3 NA 374

1H NMR (400 MHz, DMSO-d6) δ 9.23 (d, J = 7.0 Hz, 1H), 9.05 (s, 1H), 8.85(d, J = 4.1 Hz, 1H), 8.75 (d, J = 8.6 Hz, 1H), 8.61 (d, J = 5.0 Hz, 1H),7.93 (t, J = 4.4 Hz, 1H), 7.80 (d, J = 7.5 Hz, 1H), 7.72 (d, J = 7.7 Hz,1H), 7.68 (dd, J = 8.9, 4.2 Hz, 1H), 7.26 (t, J = 8.6 Hz, 2H), 7.14-7.02(m, 2H), 6.74 (d, J = 13.3 Hz, 1H), 6.68 (s, 1H), 5.03 (s, 1H), 4.85 (d,J = 9.4 Hz, 1H), 4.15 (d, J = 12.7 Hz, 1H), 3.95 (d, J = 11.2 Hz, 1H),3.84 (d, J = 10.6 Hz, 1H), 3.74 (d, J = 13.2 Hz, 2H), 775.2 NA 3.67 (s,3H), 3.55 (t, J = 11.7 Hz, 1H), 3.37 (d, J = 12.2 Hz, 1H), 3.27 (d, J =12.8 Hz, 1H), 2.11 (d, J = 6.3 Hz, 3H). 375

1H NMR (400 MHz, DMSO-d6) δ 9.05 (s, 1H), 9.00 (d, J = 7.6 Hz, 1H), 8.86(d, J = 4.2 Hz, 1H), 8.75 (s, 1H), 8.68 (d, J = 5.3 Hz, 1H), 8.60 (d, J= 5.0 Hz, 1H), 8.55 (d, J = 8.6 Hz, 1H), 8.25 (s, 1H), 7.91 (t, J = 3.7Hz, 1H), 7.76 (d, J = 7.6 Hz, 2H), 7.65 (td, J = 9.1, 3.2 Hz, 2H),6.76-6.62 (m, 2H), 4.92-4.70 (m, 2H), 4.45-4.28 (m, 2H), 4.15 (d, J =12.7 Hz, 1H), 3.95 (d, J = 10.9 Hz, 1H), 3.73 (d, J = 12.6 Hz, 1H), 3.65(s, 3H), 3.63-3.44 (m, 2H), 3.36 (d, J = 12.3 Hz, 1H), 786.2 NA 3.25 (t,J = 12.3 Hz, 1H), 3.03 (d, J = 6.2 Hz, 2H), 2.04 (d, J = 5.4 Hz, 3H).376

1H NMR (400 MHz, DMSO-d6) δ 9.05 (d, J = 4.4 Hz, 1H), 9.01 (d, J = 7.4Hz, 1H), 8.86 (d, J = 4.4 Hz, 1H), 8.68 (s, 1H), 8.59 (dd, J = 14.4, 6.8Hz, 2H), 8.30 (d, J = 8.3 Hz, 1H), 7.90 (dd, J = 4.8, 2.4 Hz, 1H), 7.77(d, J = 8.0 Hz, 2H), 7.66 (td, J = 9.4, 8.6, 5.8 Hz, 2H), 6.79-6.60 (m,3H), 4.94-4.69 (m, 2H), 4.38 (s, 1H), 4.31 (dt, J = 11.4, 6.2 Hz, 1H),4.15 (d, J = 12.6 Hz, 1H), 3.95 (d, J = 10.9 Hz, 1H), 3.73 (d, J = 12.4Hz, 1H), 3.65 (s, 3H), 3.63- 3.45 (m, 3H), 3.36 (d, J = 12.4 800.2 NAHz, 1H), 3.27 (d, J = 12.4 Hz, 1H), 3.12-2.92 (m, 2H), 2.63 (s, 3H),2.04 (d, J = 4.7 Hz, 3H). 377

1H NMR (400 MHz, DMSO-d6) δ 9.05 (d, J = 2.6 Hz, 1H), 9.01- 8.94 (m,1H), 8.84 (d, J = 3.4 Hz, 1H), 8.65 (d, J = 8.6 Hz, 1H), 8.60 (t, J =3.7 Hz, 1H), 7.91 (q, J = 3.7 Hz, 1H), 7.81-7.73 (m, 1H), 7.68 (dd, J =8.0, 2.9 Hz, 2H), 6.80-6.62 (m, 2H), 4.83 (s, 2H), 4.20-4.05 (m, 3H),3.95 (d, J = 11.4 Hz, 1H), 3.79-3.60 (m, 5H), 3.54 (s, 2H), 3.36 (d, J =12.5 Hz, 1H), 3.27 (d, J = 12.4 Hz, 1H), 2.05 (s, 3H), 1.66 (q, J = 6.8Hz, 1H), 1.51-1.35 (m, 2H), 0.89 (dd, J = 6.8, 2.3 Hz, 6H). 751.3 NA 378

1H NMR (400 MHz, DMSO-d6) δ 9.23 (d, J = 7.7 Hz, 1H), 9.06 (s, 1H), 8.87(d, J = 4.1 Hz, 1H), 8.71 (d, J = 8.7 Hz, 1H), 8.61 (d, J = 5.0 Hz, 1H),7.93 (d, J = 5.0 Hz, 1H), 7.82 (d, J = 7.5 Hz, 1H), 7.77 (d, J = 7.8 Hz,1H), 7.71 (dd, J = 8.6, 4.2 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.54-7.41(m, 2H), 7.29 (d, J = 8.1, 2.7 Hz, 1H), 6.72 (dd, J = 13.2, 6.7 Hz, 1H),6.66 (s, 1H), 5.24-.12 (m, 1H), 4.91-4.76 (m, 1H), 4.14 (d, J = 12.6 Hz,1H), 4.00-3.87 (m, 2H), 3.72 (d, 2H), 3.67 (s, 3H), 3.54 (t, J = 3.0 Hz,1H), 3.34 (d, 1H), 3.25 (t, 1H), 2.05 (d, J = 7.6 Hz, 3H). 841.1 NA 379

1H NMR (400 MHz, DMSO-d6) δ 9.04 (s, 1H), 8.99 (d, J = 7.8 Hz, 1H), 8.84(d, J = 4.2 Hz, 1H), 8.65 (d, J = 8.7 Hz, 1H), 8.60 (d, J = 5.0 Hz, 1H),7.91 (d, J = 4.3 Hz, 1H), 7.76 (d, J = 7.6 Hz, 1H), 7.67 (d, J = 8.0 Hz,2H), 6.71 (d, J = 13.4 Hz, 1H), 6.65 (s, 1H), 4.86 (s, 2H), 4.14 (d, J =12.7 Hz, 1H), 3.98-3.82 (m, 3H), 3.73 (d, J = 13.3 Hz, 2H), 3.66 (s,3H), 3.53 (d, J = 9.2 Hz, 2H), 3.36 (d, J = 12.5 Hz, 1H), 3.27 (d, J =12.7 Hz, 1H), 2.03 (d, J = 6.9 Hz, 3H), 1.89 (p, J = 6.6 Hz, 1H), 0.90(d, J = 6.7 Hz, 6H). 737.3 NA 380

1H NMR (400 MHz, DMSO-d6) δ 9.20 (d, J = 7.1 Hz, 1H), 9.05 (s, 1H),8.90-8.82 (m, 1H), 8.75 (d, J = 8.6 Hz, 1H), 8.64-8.57 (m, 1H), 7.92 (d,J = 5.0 Hz, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H),7.68 (dd, J = 8.7, 4.2 Hz, 1H), 7.24 (d, J = 8.1 Hz, 1H), 6.88 (s, 1H),6.81- 6.69 (m, 2H), 6.68 (s, 1H), 5.00 (d, J = 8.7 Hz, 2H), 4.85 (d, J =9.7 Hz, 1H), 4.15 (d, J = 12.6 Hz, 1H), 3.95 (d, J = 11.5 Hz, 1H), 3.84(dd, J = 14.6, 5.7 Hz, 1H), 3.73 (d, J = 10.6 Hz, 2H), 3.67 797.3 NA (s,3H), 3.55 (t, J = 11.4 Hz, 1H), 3.42-3.32 (m, 1H), 3.26 (t, J = 12.1 Hz,1H), 2.85 (q, J = 8.1 Hz, 4H), 2.11 (d, J = 6.3 Hz, 3H), 2.04 (p, J =7.5 Hz, 2H). 381

1H NMR (400 MHz, DMSO-d6) δ 9.12-8.95 (m, 2H), 8.84 (d, J = 4.2 Hz, 1H),8.65 (d, J = 8.7 Hz, 1H), 8.60 (d, J = 5.1 Hz, 1H), 7.97-7.86 (m, 1H),7.76 (d, J = 7.5 Hz, 1H), 7.67 (d, J = 7.8 Hz, 2H), 6.71 (dd, J = 20.6,7.9 Hz, 2H), 4.82 (d, J = 8.7 Hz, 2H), 4.21 (t, J = 5.0 Hz, 2H), 4.15(d, J = 12.6 Hz, 1H), 3.95 (d, J = 11.2 Hz, 1H), 3.73 (d, J = 14.0 Hz,2H), 3.52 (d, J = 7.9 Hz, 4H), 3.36 (d, J = 12.6 Hz, 1H), 3.27 (d, J =1.5 Hz, 4H), 2.09 (d, J = 6.3 Hz, 3H). 739.2 NA 382

1H NMR (400 MHz, DMSO-d6) δ 9.05 (s, 1H), 8.98 (d, J = 7.7 Hz, 1H), 8.86(d, J = 4.1 Hz, 1H), 8.67 (d, J = 8.6 Hz, 1H), 8.60 (d, J = 5.0 Hz, 1H),7.91 (t, J = 4.2 Hz, 1H), 7.77 (d, J = 7.5 Hz, 1H), 7.68 (d, J = 7.7 Hz,2H), 6.81- 6.57 (m, 2H), 4.84 (dt, J = 10.6, 6.3 Hz, 2H), 4.15 (d, J =12.7 Hz, 1H), 4.07 (q, J = 6.4 Hz, 2H), 3.95 (dd, J = 11.5, 3.5 Hz, 1H),3.72 (dd, J = 14.4, 5.6 Hz, 2H), 3.53 (tt, J = 9.3, 5.5 Hz, 2H), 3.36(d, J = 12.4 Hz, 1H), 3.30- 3.18 (m, 1H), 2.06 (s, 3H), 1.55 (p, J = 6.8Hz, 2H), 1.25 (d, J = 13.8 Hz, 14H), 0.83 (t, J = 6.5 Hz, 3H). 821.4 NA383

1H NMR (400 MHz, DMSO-d6) δ 9.26 (d, J = 6.9 Hz, 1H), 9.06 (s, 1H), 8.86(d, J = 4.1 Hz, 1H), 8.77 (d, J = 8.7 Hz, 1H), 8.61 (d, J = 5.0 Hz, 1H),7.93 (d, J = 4.9 Hz, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.77-7.65 (m, 2H),7.45 (d, J = 8.4 Hz, 2H), 7.16 (dd, J = 9.0, 3.5 Hz, 2H), 6.78-6.71 (m,1H), 6.68 (s, 1H), 5.04 (d, J = 7.2 Hz, 1H), 4.91-4.79 (m, 1H), 4.15 (d,J = 12.6 Hz, 1H), 3.95 (d, J = 11.3 Hz, 1H), 3.85 (d, J = 9.5 Hz, 1H),3.74 (d, J = 13.1 Hz, 2H), 3.67 (s, 3H), 3.55 (t, J = 11.5 Hz, 1H), 3.37(d, J = 12.4 Hz, 1H), 3.26 (t, J = 12.4 Hz, 1H), 2.12 (d, J = 6.2 Hz,3H). 841.1 NA 384

1H NMR (400 MHz, DMSO-d6) δ 9.66 (s, 1H), 9.07 (d, J = 7.2 Hz, 2H), 8.86(s, 1H), 8.63 (dd, J = 16.9, 6.9 Hz, 2H), 7.91 (s, 1H), 7.78 (d, J = 7.6Hz, 1H), 7.67 (d, J = 7.1 Hz, 2H), 6.79-6.65 (m, 2H), 4.84 (s, 2H), 4.16(d, J = 12.5 Hz, 2H), 4.08-3.90 (m, 4H), 3.79-3.48 (m, 8H), 3.37 (d, J =11.6 Hz, 3H), 3.27 (d, J = 13.1 Hz, 1H), 3.13-2.92 (m, 5H), 2.11 (d, J =5.1 Hz, 3H), 1.94 (s, 2H). 808.0 NA 385

1H NMR (400 MHz, DMSO-d6) δ 9.03 (d, J = 16.1 Hz, 2H), 8.86 (d, J = 4.2Hz, 1H), 8.69-8.56 (m, 2H), 7.92 (d, J = 4.7 Hz, 1H), 7.78 (d, J = 7.6Hz, 1H), 7.69 (dd, J = 7.9, 4.8 Hz, 2H), 6.71 (dt, J = 24.9, 7.3 Hz,3H), 4.84 (d, J = 9.1 Hz, 2H), 4.15 (d, J = 12.7 Hz, 1H), 3.95 (d, J =11.4 Hz, 1H), 3.78-3.62 (m, 5H), 3.61-3.43 (m, 2H), 3.36 (d, J = 12.5Hz, 1H), 3.27 (d, J = 12.6 Hz, 1H), 2.34 (ddd, J = 20.9, 13.2, 7.6 Hz,1H), 2.08 (s, 1H), 2.02 (s, 1H), 1.81 (s, 4H), 1.74 (d, J = 5.7 Hz, 1H),1.65 (s, 2H), 1.57 (dd, J = 10.5, 4.6 Hz, 1H), 1.50 (d, J = 5.4 Hz, 1H),1.30 (tq, J = 20.3, 9.9, 9.4 Hz, 6H). 835.0 NA 386

1H NMR (400 MHz, DMSO-d6) δ 9.06 (d, J = 7.0 Hz, 2H), 8.86 (d, J = 4.2Hz, 1H), 8.66 (d, J = 8.6 Hz, 1H), 8.60 (d, J = 4.9 Hz, 1H), 7.92 (t, J= 4.6 Hz, 1H), 7.80- 7.66 (m, 3H), 6.73-6.62 (m, 2H), 5.06 (d, J = 14.8Hz, 1H), 4.95-4.77 (m, 3H), 4.15 (d, J = 12.6 Hz, 1H), 4.01-3.90 (m,2H), 3.73 (d, J = 12.7 Hz, 1H), 3.66 (t, J = 2.0 Hz, 3H), 3.53 (qd, J =14.9, 13.4, 6.7 Hz, 2H), 3.36 (d, J = 12.3 Hz, 1H), 3.25 (t, J = 12.5Hz, 1H), 2.98 (s, 3H), 2.88 (s, 3H), 2.02 (s, 3H). 766.6 NA 387

1H NMR (400 MHz, DMSO-d6) δ 9.05 (s, 1H), 8.98 (d, J = 7.9 Hz, 1H), 8.85(d, J = 4.2 Hz, 1H), 8.65 (d, J = 8.7 Hz, 1H), 8.60 (d, J = 5.0 Hz, 1H),7.91 (dd, J = 5.1, 2.5 Hz, 1H), 7.76 (d, J = 7.5 Hz, 1H), 7.69 (d, J =7.6 Hz, 2H), 6.74-6.61 (m, 2H), 4.86 (s, 2H), 4.75 (q, J = 6.7, 6.2 Hz,1H), 4.15 (d, J = 12.6 Hz, 1H), 3.95 (d, J = 10.2 Hz, 1H), 3.73 (d, J =13.3 Hz, 2H), 3.53 (q, J = 11.6 Hz, 2H), 3.36 (d, J = 12.7 Hz, 1H), 3.25(t, J = 12.7 Hz, 1H), 2.03 (s, 3H), 1.54 (dtt, J = 29.8, 14.0, 7.1 Hz,4H), 0.89 (t, J = 7.4 Hz, 3H), 0.82 (t, J = 7.5 Hz, 3H). 751.3 NA 388

1H NMR (400 MHz, DMSO-d6) δ 9.05 (s, 1H), 8.98 (d, J = 8.0 Hz, 1H),8.86-8.83 (m, 1H), 8.65 (d, J = 9.0 Hz, 1H), 8.60 (d, J = 5.1 Hz, 1H),7.91 (d, J = 4.9 Hz, 1H), 7.76 (d, J = 7.6 Hz, 1H), 7.68 (d, J = 7.9 Hz,2H), 6.71 (d, J = 13.3 Hz, 1H), 6.67 (s, 1H), 4.82 (d, J = 22.8 Hz, 3H),4.15 (d, J = 12.6 Hz, 1H), 3.95 (d, J = 13.7 Hz, 1H), 3.76-3.68 (m, 2H),3.65 (s, 3H), 3.53 (q, J = 11.1, 10.3 Hz, 2H), 3.36 (d, J = 13.6 Hz,1H), 3.30-3.20 (m, 1H), 2.07 (s, 3H), 1.58-1.50 (m, 2H), 1.07 (d, J =6.2 Hz, 3H), 0.87 (t, J = 7.3 Hz, 3H). 737.2 NA 389

1H NMR (400 MHz, DMSO-d6) δ 9.33 (s, 1H), 9.26 (d, J = 6.8 Hz, 1H), 9.06(s, 1H), 8.86 (d, J = 4.1 Hz, 1H), 8.73 (d, J = 8.6 Hz, 1H), 8.61 (d, J= 4.9 Hz, 1H), 7.92 (d, J = 5.1 Hz, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.74(d, J = 7.6 Hz, 1H), 7.68 (dd, J = 8.9, 4.1 Hz, 1H), 7.55 (t, J = 7.9Hz, 1H), 7.44 (d, J = 7.8 Hz, 1H), 7.25 (s, 1H), 7.13 (d, J = 8.3 Hz,1H), 6.74 (d, J = 13.4 Hz, 1H), 6.69 (s, 1H), 5.04 (d, J = 8.3 Hz, 1H),4.85 (d, J = 9.1 Hz, 1H), 4.35 (d, J = 5.3 Hz, 2H), 4.16 (d, J = 12.7Hz, 1H), 3.96 (d, J = 11.1 Hz, 1H), 3.90-3.80 (m, 1H), 3.76 (t, J = 12.0Hz, 2H), 3.67 (s, 3H), 3.55 (t, J = 11.5 Hz, 1H), 3.37 (d, J = 12.2 Hz,1H), 3.27 (d, J = 12.4 Hz, 1H), 3.08 (s, 4H), 2.13 (d, J = 5.0 Hz, 3H),1.22 (t, J = 7.2 Hz, 6H). 842.3 NA 390

1H NMR (400 MHz, DMSO-d6) δ 9.02 (d, J = 19.3 Hz, 2H), 8.86 (d, J = 4.1Hz, 1H), 8.69 (d, J = 8.7 Hz, 1H), 8.60 (d, J = 5.0 Hz, 1H), 7.92 (dt, J= 4.8, 2.1 Hz, 1H), 7.78 (d, J = 7.4 Hz, 1H), 7.72-7.60 (m, 2H),6.75-6.57 (m, 2H), 4.84 (d, J = 7.6 Hz, 2H), 4.15 (d, J = 12.7 Hz, 1H),3.94 (t, J = 7.0 Hz, 3H), 3.76-3.59 (m, 5H), 3.54 (dd, J = 13.9, 10.1Hz, 2H), 3.31 (dd, J = 36.7, 12.3 Hz, 2H), 2.09 (s, 3H), 1.10-0.98 (m,1H), 0.51 (d, J = 7.9 Hz, 2H), 0.27 (d, J = 4.5 Hz, 2H). 735.3 NA 391

1H NMR (400 MHz, DMSO-d6) δ 9.04 (s, 1H), 8.96 (d, J = 7.9 Hz, 1H), 8.84(d, J = 4.1 Hz, 1H), 8.65 (d, J = 8.7 Hz, 1H), 8.60 (d, J = 4.9 Hz,1H),7.91 (d, J = 4.7 Hz, 1H), 7.76 (d, J = 7.2 Hz, 1H), 7.68 (d, J = 7.5Hz, 2H), 6.72 (s, 1H), 6.65 (s, 1H), 4.88-4.79 (m, 3H), 4.15 (d, J =12.5 Hz, 1H), 3.95 (d, J = 10.8 Hz, 1H), 3.75 (s, 2H), 3.65 (s, 3H),3.56-3.48 (m, 2H), 3.36 (d, J = 10.2 Hz, 1H), 3.25 (t, J = 11.4 Hz, 1H),2.04 (s, 3H), 1.58-1.47 (m, 2H), 1.22 (d, J = 6.1 Hz, 3H), 0.87- 0.81(m, 3H). 737.2 NA 392

1H NMR (400 MHz, DMSO-d6) δ 9.06 (d, J = 7.8 Hz, 2H), 8.86 (d, J = 4.1Hz, 1H), 8.64 (d, J = 8.7 Hz, 1H), 8.60 (d, J = 5.1 Hz, 1H), 7.91 (d, J= 4.9 Hz, 1H), 7.76 (dd, J = 9.5, 7.6 Hz, 2H), 7.71- 7.67 (m, 1H), 6.69(d, J = 13.7 Hz, 1H), 6.66 (s, 1H), 5.08 (d, J = 14.9 Hz, 1H), 4.92 (d,J = 14.9 Hz, 2H), 4.85 (d, J = 16.2 Hz, 2H), 4.15 (d, J = 12.6 Hz, 1H),3.97 (s, 1H), 3.93 (s, 1H), 3.73 (d, J = 12.7 Hz, 1H), 3.66 (d, J = 2.3Hz, 3H), 3.64-3.55 (m, 4H), 3.48 (dd, J = 23.3, 15.5 Hz, 5H), 3.36 (d, J= 12.4 Hz, 1H), 3.26 (d, J = 12.6 Hz, 1H), 2.02 (s, 3H). 808.3 NA 393

1H NMR (400 MHz, DMSO-d6) δ 9.02 (d, J = 16.9 Hz, 2H), 8.85 (d, J = 3.9Hz, 1H), 8.66-8.57 (m, 2H), 7.92 (d, J = 4.9 Hz, 1H), 7.81-7.73 (m, 1H),7.68 (d, J = 8.8 Hz, 2H), 6.71-6.62 (m, 2H), 4.93-4.75 (m, 3H), 4.15 (d,J = 12.6 Hz, 1H), 3.95 (d, J = 11.1 Hz, 1H), 3.73 (d, J = 13.5 Hz, 6H),3.53 (q, J = 14.6, 13.8 Hz, 2H), 3.36 (d, J = 12.8 Hz, 1H), 3.26 (d, J =12.5 Hz, 1H), 2.03 (d, J = 23.8 Hz, 3H), 1.57-1.31 (m, 3H), 1.25 (dd, J= 6.3, 2.9 Hz, 6H). 811.3 NA 394

1H NMR (400 MHz, DMSO-d6) δ 9.10-8.99 (m, 2H), 8.85 (t, J = 3.0 Hz, 1H),8.62 (dd, J = 16.4, 6.9 Hz, 2H), 7.92 (d, J = 4.9 Hz, 1H), 7.77 (d, J =7.5 Hz, 1H), 7.67 (dd, J = 8.9, 4.9 Hz, 2H), 6.66 (d, J = 8.2 Hz, 2H),4.86 (s, 1H), 4.62-4.57 (m, 1H), 4.15 (d, J = 12.6 Hz, 1H), 3.95 (d, J =11.4 Hz, 1H), 3.73 (d, J = 13.3 Hz, 5H), 3.54 (t, J = 12.6 Hz, 2H), 3.36(d, J = 12.6 Hz, 1H), 3.26 (d, J = 12.5 Hz, 1H), 2.03 (d, J = 22.0 Hz,3H), 1.84 (d, J = 7.9 Hz, 2H), 1.76 (dd, J = 5.8, 2.0 Hz, 2H), 1.64 (s,2H), 1.53 (d, J = 5.5 Hz, 2H), 1.48-1.41 (m, 3H), 1.36 (t, J = 8.1 Hz,3H), 1.26-1.20 (m, 1H). 851.3 NA 395

1H NMR (400 MHz, DMSO-d6) δ 9.17 (s, 1H), 9.14-9.00 (m, 2H), 8.86 (t, J= 2.7 Hz, 1H), 8.66 (d, J = 8.8 Hz, 1H), 8.63-8.54 (m, 1H), 7.91 (d, J =5.0 Hz, 1H), 7.78 (dd, J = 7.6, 1.9 Hz, 1H), 7.67 (d, J = 7.6 Hz, 2H),6.77- 6.66 (m, 2H), 4.88 (dd, J = 20.8, 9.6 Hz, 2H), 4.40 (s, 1H), 4.32(s, 1H), 4.16 (d, J = 12.6 Hz, 1H), 3.96 (d, J = 11.8 Hz, 1H), 3.74 (d,J = 11.3 Hz, 2H), 3.56 (dd, J = 23.8, 12.5 Hz, 2H), 3.47- 3.34 (m, 3H),3.32-3.17 (m, 3H), 2.94 (d, J = 11.3 Hz, 1H), 2.84 (s, 1H), 2.11 (s,3H), 1.77 (t, J = 16.7 Hz, 2H), 1.67-1.52 (m, 3H), 1.33 (d, J = 12.7 Hz,1H). 792.3 NA 396

1H NMR (400 MHz, DMSO-d6) δ 9.24 (d, J = 6.8 Hz, 1H), 9.06 (s, 1H), 8.86(t, J = 3.0 Hz, 1H), 8.76 (d, J = 8.7 Hz, 1H), 8.65- 8.57 (m, 1H), 7.93(d, J = 5.0 Hz, 1H), 7.81 (d, J = 7.5 Hz, 1H), 7.71 (dd, J = 17.1, 7.8Hz, 2H), 7.33 (d, J = 8.1 Hz, 1H), 6.90 (dd, J = 15.0, 5.8 Hz, 2H), 6.75(d, J = 13.1 Hz, 1H), 6.69 (s, 1H), 5.03 (m, 1H), 4.99 (s, 4H),4.88-4.86 (m, 1H), 4.15 (d, J = 12.7 Hz, 1H), 3.96 (d, J = 11.4 Hz, 1H),3.84-3.69 (m, 3H), 3.67 (s, 3H), 3.55 (t, J = 11.7 Hz, 1H), 3.37 (d, J =12.4 Hz, 1H), 3.26 (t, J = 12.9 Hz, 1H), 2.14 (d, J = 5.4 Hz, 3H). 799.2NA 397

1H NMR (400 MHz, DMSO-d6) δ 9.17 (d, J = 7.4 Hz, 1H), 9.06 (s, 1H), 8.87(s, 1H), 8.77 (d, J = 8.5 Hz, 1H), 8.61 (s, 1H), 7.92 (s, 1H), 7.76 (dt,J = 25.0, 12.6 Hz, 3H), 7.02 (d, J = 8.5 Hz, 1H), 6.91 (d, J = 10.1 Hz,2H), 6.73 (d, J = 13.9 Hz, 1H), 6.67 (s, 1H), 5.03 (s, 1H), 4.85 (s,1H), 4.15 (d, J = 12.7 Hz, 1H), 3.95 (d, J = 11.0 Hz, 1H), 3.86 (s, 2H),3.83 (s, 3H), 3.73 (d, J = 12.4 Hz, 1H), 3.66 (s, 3H), 3.54 (s, 1H),3.36 (d, J = 10.4 Hz, 1H), 3.32-3.12 (m, 1H), 2.08 (d, J = 7.2 Hz, 3H),1.32 (s, 9H). 843.1 NA 398

1H NMR (400 MHz, DMSO-d6) δ 9.00 (d, J = 7.8 Hz, 1H), 8.88- 8.81 (m,1H), 8.67 (d, J = 8.6 Hz, 1H), 8.61 (ddd, J = 4.4, 2.1, 1.3 Hz, 1H),8.08 (dd, J = 8.8, 1.3 Hz, 1H), 7.87 (dd, J = 8.6, 4.4 Hz, 1H), 7.76 (d,J = 7.5 Hz, 1H), 7.67 (dt, J = 7.8, 3.3 Hz, 2H), 6.70 (dd, J = 13.0, 2.3Hz, 1H), 6.66 (d, J = 2.4 Hz, 1H), 4.86 (d, J = 4.3 Hz, 1H), 4.83 (m,1H), 4.14 (d, J = 12.6 Hz, 1H), 3.95 (dd, J = 11.3, 3.7 Hz, 1H), 3.78-3.70 (m, 2H), 3.69 (d, J = 3.6 Hz, 3H), 3.57 (d, J = 2.4 Hz, 3H), 3.53(d, J = 3.7 Hz, 1H), 3.51 (d, J = 9.9 Hz, 1H), 3.36 (d, J = 12.3 Hz,1H), 3.25 (t, J = 12.2 Hz, 1H), 2.05 (s, 3H). 695.2 NA 399

1H NMR (400 MHz, DMSO-d6) δ 13.11-12.65 (s, 1H), 8.87 (d, J = 8.1 Hz,1H), 8.85-8.83 (m, 1H), 8.73-8.65 (m, 1H), 8.61 (ddd, J = 4.4, 2.3, 1.2Hz, 1H), 8.08 (dd, J = 8.8, 1.3 Hz, 1H), 7.87 (dd, J = 8.6, 4.4 Hz, 1H),7.75 (d, J = 7.6 Hz, 1H), 7.71-7.63 (m, 2H), 6.69 (d, J = 13.4 Hz, 1H),6.65 (s, 1H), 4.88-4.80 (m, 1H), 4.77 (d, J = 11.5 Hz, 1H), 4.14 (d, J =12.6 Hz, 1H), 3.94 (dd, J = 11.4, 3.6 Hz, 1H), 3.81-3.68 (m, 2H), 3.57(d, J = 2.5 Hz, 3H), 3.55- 3.42 (m, 2H), 3.35 (d, J = 12.4 Hz, 1H), 3.25(t, J = 12.1 Hz, 1H), 2.03 (d, J = 2.5 Hz, 3H). 681.2 0.1 400

1H NMR (400 MHz, DMSO-d6) δ 9.10 (d, J = 3.0 Hz, 1H), 9.00 (d, J = 7.7Hz, 1H), 8.88-8.80 (m, 2H), 8.66 (dd, J = 8.7, 1.6 Hz, 1H), 7.76 (d, J =7.6 Hz, 1H), 7.67 (td, J = 5.8, 5.3, 2.6 Hz, 2H), 7.61 (d, J = 6.1 Hz,1H), 6.74-6.59 (m, 2H), 4.88-4.78 (m, 2H), 4.15 (d, J = 12.7 Hz, 1H),3.97-3.87 (m, 1H), 3.77- 3.64 (m, 5H), 3.57 (d, J = 2.2 Hz, 5H), 3.36(d, J = 12.3 Hz, 1H), 3.25 (t, J = 12.1 Hz, 1H), 2.05 (s, 3H). 695.2 NA401

1H NMR (400 MHz, DMSO-d6) δ 9.10 (d, J = 3.6 Hz, 1H), 8.95- 8.76 (m,3H), 8.68 (d, J = 8.7 Hz, 1H), 7.76 (d, J = 7.5 Hz, 1H), 7.74-7.56 (m,3H), 6.74-6.56 (m, 2H), 4.90-4.72 (m, 2H), 4.14 (d, J = 12.6 Hz, 1H),3.94 (dd, J = 11.4, 3.6 Hz, 1H), 3.75 (t, J = 13.4 Hz, 2H), 3.57 (d, J =2.4 Hz, 3H), 3.55-3.48 (m, 1H), 3.47 (s, 1H), 3.35 (d, J = 12.6 Hz, 1H),3.25 (t, J = 12.4 Hz, 1H), 2.03 (s, 3H). 681.2 0.1 402

1H NMR (400 MHz, DMSO-d6) δ 8.86 (d, J = 8.0 Hz, 3H), 8.68 (d, J = 8.4Hz, 1H), 8.42 (d, J = 9.3 Hz, 1H), 7.76 (d, J = 7.5 Hz, 1H), 7.70-7.63(m, 2H), 7.45-7.39 (m, 1H), 6.73-6.63 (m, 2H), 4.87-4.72 (m, 3H), 4.14(d, J = 2.6 Hz, 1H), 3.99-3.91 (m, 2H), 3.74 (s, 2H), 3.63 (s, 3H),3.58-3.51 (m, 1H), 3.50-3.42 (m, 1H), 3.38-3.31 (m, 1H), 3.28-3.21 (m,1H), 2.03 (s, 3H). 681.2 0.1 403

1H NMR (400 MHz, DMSO-d6) δ 9.00 (d, J = 7.8 Hz, 1H), 8.92- 8.86 (m,2H), 8.73-8.68 (m, 2H), 7.78 (d, J = 7.5 Hz, 1H), 7.73-7.67 (m, 2H),6.74-6.64 (m, 2H), 4.90-4.79 (m, 2H), 4.15 (d, J = 12.6 Hz, 1H), 3.95(dd, J = 11.5, 3.5 Hz, 1H), 3.80- 3.65 (m, 5H), 3.61 (s, 3H), 3.55 (t, J= 13.9, 7.6, 2.5 Hz, 2H), 3.36 (d, J = 11.8 Hz, 1H), 3.25 (t, 1H), 2.05(s, 3H). 696.8 NA 404

1H NMR (400 MHz, DMSO-d6) δ 8.93-8.83 (m, 3H), 8.75-8.67 (m, 2H), 7.77(d, J = 7.5 Hz, 1H), 7.74-7.66 (m, 2H), 6.73-6.62 (m, 2H), 4.89-4.75 (m,2H), 4.14 (d, J = 12.6 Hz, 1H), 3.94 (dd, J = 11.7, 3.5 Hz, 1H), 3.81-3.69 (m, 2H), 3.61 (s, 3H), 3.59- 3.43 (m, 2H), 3.35 (d, J = 12.2 Hz,1H), 3.25 (t, 1H), 2.03 (d, J = 2.4 Hz, 3H). 682.7 0.1 405

1H NMR (400 MHz, DMSO-d6) δ 9.32 (s, 1H), 9.26-9.18 (m, 1H), 8.99 (d, J= 7.8 Hz, 1H), 8.91- 8.84 (m, 1H), 8.67 (d, J = 8.7 Hz, 1H), 7.82-7.73(m, 1H), 7.72- 7.63 (m, 2H), 6.76-6.64 (m, 2H), 4.88-4.80 (m, 2H), 4.15(d, J = 12.6 Hz, 1H), 3.98-3.91 (m, 1H), 3.78-3.70 (m, 2H), 3.68 (s,3H), 3.61 (s, 3H), 3.58- 3.51 (m, 2H), 3.42-3.32 (m, 1H), 3.30-3.18 (m,1H), 2.04 (s, 3H). 696.8 NA 406

1H NMR (400 MHz, DMSO-d6) δ 9.32 (s, 1H), 9.25-9.18 (m, 1H), 8.91-8.82(m, 2H), 8.69 (d, J = 8.6 Hz, 1H), 7.80-7.73 (m, 1H), 7.73-7.64 (m, 2H),6.75-6.60 (m, 2H), 4.90-4.74 (m, 2H), 4.14 (d, J = 12.6 Hz, 1H), 3.95(d, J = 10.8 Hz, 1H), 3.81-3.68 (m, 2H), 3.60 (s, 3H), 3.58-3.40 (m,2H), 3.39-3.31 (m, 1H), 3.31-3.18 (m, 1H), 2.02 (s, 3H). 682.2 0.08 407

1H NMR (400 MHz, Chloroform- d) δ 8.84-8.72 (m, 2H), 8.66 (d, J = 8.6Hz, 1H), 8.55 (s, 1H), 8.00 (s, 1H), 7.58 (s, 2H), 7.44 (dd, J = 8.6,4.2 Hz, 1H), 6.66 (d, J = 6.5 Hz, 1H), 6.46 (s, 1H), 6.37 (d, J = 13.6Hz, 1H), 5.08 (d, J = 7.0 Hz, 1H), 4.29 (d, J = 12.4 Hz, 1H), 4.11 (dd,J = 8.2, 3.8 Hz, 1H), 4.04 (dd, J = 11.3, 3.5 Hz, 1H), 3.84-3.70 (m,3H), 3.68 (s, 3H), 3.65-3.56 (m, 1H), 3.50 (t, J = 12.0 Hz, 1H), 3.26(d, J = 12.2 Hz, 1H), 2.38 (s, 3H). 681.2 0.162 408

1H NMR (400 MHz, Chloroform- d) δ 8.8-8.72 (m, 2H), 8.64 (d, J = 8.6 Hz,1H), 8.56 (d, J = 5.0 Hz, 1H), 8.03 (d, J = 5.0 Hz, 1H), 7.59 (q, J =7.6 Hz, 2H), 7.46 (dd, J = 8.6, 4.2 Hz, 1H), 6.63 (d, J = 6.1 Hz, 1H),6.47 (s, 1H), 6.38 (dd, J = 13.4, 2.4 Hz, 1H), 5.13-5.02 (m, 1H), 4.30(d, J = 12.4 Hz, 1H), 4.12 (dd, J = 8.0, 3.8 Hz, 1H), 4.04 (dd, J =11.2, 3.5 Hz, 1H), 3.86-3.78 (m, 1H), 3.72 (t, J = 5.6 Hz, 2H), 3.69 (s,3H), 3.65-3.59 (m, 1H), 3.51 (t, J = 11.7 Hz, 1H), 3.27 (d, J = 12.3 Hz,1H), 2.39 (s, 3H). 681.2 0.049 409

1H NMR (400 MHz, DMSO-d6) δ 13.21-12.53 (s, 1H), 9.05 (s, 1H), 8.87 (d,J = 7.9 Hz, 1H), 8.84 (dd, J = 4.2, 1.4 Hz, 1H), 8.71- 8.65 (m, 1H),8.60 (dd, J = 4.9, 1.8 Hz, 1H), 7.91 (ddd, J = 5.0, 3.4, 0.7 Hz, 1H),7.76 (d, J = 7.6 Hz, 1H), 7.71-7.65 (m, 2H), 6.70 (d, J = 13.1 Hz, 1H),6.64 (s, 1H), 4.83 (d, J = 6.1 Hz, 1H), 4.81-4.73 (m, 1H), 4.14 (d, J =12.6 Hz, 1H), 3.94 (dd, J = 11.2, 3.6 Hz, 1H), 3.81-3.69 (m, 2H), 3.66(d, J = 2.6 Hz, 3H), 3.60- 3.51 (m, 1H), 3.46 (dd, J = 14.7, 10.6 Hz,1H), 3.35 (d, J = 12.3 Hz, 1H), 3.25 (t, J = 12.2 Hz, 1H), 2.08-2.01 (m,3H). 681.2 0.401 410

1H NMR (400 MHz, DMSO-d6) δ 8.91-8.82 (m, 2H), 8.68 (d, J = 8.6 Hz, 1H),7.73 (d, 1H), 7.71- 7.63 (m, 2H), 6.72-6.61 (m, 2H), 4.92-4.71 (m, 2H),4.14 (d, J = 12.6 Hz, 1H), 3.94 (d, J = 11.4 Hz, 1H), 3.80-3.68 (m, 2H),3.61 (s, 3H), 3.59-3.40 (m, 2H), 3.35 (d, J = 12.7 Hz, 1H), 3.26 (t,1H), 2.86 (d, J = 1.9 Hz, 3H), 2.01 (d, 3H). 701.7 0.054 411

1H NMR (400 MHz, DMSO-d6) δ 8.89-8.82 (m, 2H), 8.65 (d, J = 8.4 Hz, 1H),7.67 (d, J = 3.8 Hz, 1H), 7.62 (s, 2H), 6.68 (d, J = 13.1 Hz, 1H), 6.64(s, 1H), 4.84 (d, J = 2.8 Hz, 1H), 4.78-4.72 (m, 1H), 4.71-4.61 (m, 2H),4.16 (s, 1H), 3.93 (s, 1H), 3.82 (s, 2H), 3.73 (d, J = 14.0 Hz, 2H),3.55 (d, J = 11.7 Hz, 1H), 3.50-3.38 (m, 1H), 3.35 (d, J = 12.4 Hz, 1H),3.25 (s, 4H), 2.34 (d, J = 8.3 Hz, 2H), 2.03 (s, 3H). 686.2 0.06 412

1H NMR (400 MHz, DMSO-d6) δ 8.88-8.82 (m, 2H), 8.64 (d, J = 9.0 Hz, 1H),7.68-7.64 (m, 1H), 7.62 (s, 2H), 6.68 (d, J = 13.3 Hz, 1H), 6.64 (s,1H), 4.88- 4.79 (m, 1H), 4.79-4.70 (m, 1H), 4.30 (m, 2H), 4.14 (d, J =12.9 Hz, 1H), 3.93 (m, 3H), 3.73 (d, J = 14.6 Hz, 2H), 3.55 (d, J = 8.1Hz, 1H), 3.49-3.38 (m, 2H), 3.34 (s, 3H), 3.24 (t, J = 13.0 Hz, 1H),2.87-2.68 (m, 1H), 2.02 (s, 3H). 686.2 0.091 413

1H NMR (400 MHz, DMSO-d6) δ 8.86 (t, J = 5.9 Hz, 2H), 8.68 (d, J = 8.6Hz, 1H), 8.10 (d, J = 1.6 Hz, 1H), 7.67 (td, J = 8.1, 4.9 Hz, 3H),6.73-6.60 (m, 2H), 4.90- 4.71 (m, 2H), 4.14 (d, J = 12.6 Hz, 1H), 4.05(s, 3H), 3.99- 3.91 (m, 1H), 3.74 (d, J = 12.8 Hz, 2H), 3.50 (ddd, J =35.8, 13.4, 9.9 Hz, 2H), 3.37 (d, J = 2.3 Hz, 4H), 3.25 (t, J = 12.5 Hz,1H), 2.03 (s, 3H). 684.3 0.529 414

1H NMR (400 MHz, DMSO-d6) δ 9.12 (d, J = 8.2 Hz, 1H), 9.05 (d, J = 1.6Hz, 1H), 8.88 (d, J = 4.0 Hz, 1H), 8.76 (t, J = 7.7 Hz, 1H), 8.61 (d, J= 5.0 Hz, 1H), 7.92 (p, J = 2.0 Hz, 1H), 7.79 (dd, J = 7.7, 2.5 Hz, 1H),7.72 (t, J = 5.9 Hz, 2H), 6.91 (t, J = 6.2 Hz, 2H), 4.92 (h, J = 7.9 Hz,1H), 4.87- 4.75 (m, 1H), 4.15 (d, J = 12.7 Hz, 1H), 3.95 (dd, J = 11.7,3.6 Hz, 1H), 3.86-3.69 (m, 2H), 3.60-3.34 (m, 3H), 3.25 (t, J = 12.2 Hz,1H). 701.1 0.048 415

1H NMR (400 MHz, DMSO-d6) δ 8.86 (d, J = 8.0 Hz, 2H), 8.70 (d, J = 8.6Hz, 1H), 8.34-8.30 (m, 1H), 7.75 (d, 1H), 7.72-7.65 (m, 2H), 7.46-7.42(m, 1H), 6.73-6.62 (m, 2H), 4.90-4.73 (m, 2H), 4.14 (d, J = 12.7 Hz,1H), 4.06 (s, 3H), 3.94 (d, J = 11.2 Hz, 1H), 3.75 (t, 2H), 3.62- 3.41(m, 5H), 3.35 (d, J = 12.3 Hz, 1H), 3.26 (t, 1H), 2.03 (s, 3H). 711.30.091 416

1H NMR (400 MHz, DMSO-d6) δ 8.90-8.82 (m, 2H), 8.68 (d, J = 8.6 Hz, 1H),8.57 (s, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.67 (d, J = 7.8 Hz, 2H), 7.04(t, J = 2.5 Hz, 1H), 6.72-6.62 (m, 2H), 4.82 (s, 1H), 4.79 (d, J = 8.9Hz, 1H), 4.14 (d, J = 12.6 Hz, 1H), 3.94 (d, J = 11.3 Hz, 1H), 3.80-3.67(m, 2H), 3.60-3.53 (m, 4H), 3.47 (dd, J = 23.9, 11.6 Hz, 1H), 3.35 (d, J= 12.4 Hz, 1H), 3.26 (d, J = 12.0 Hz, 1H), 3.09 (s, 6H), 2.02 (s, 3H).724.2 0.126 417

1H NMR (400 MHz, DMSO-d6) δ 13.12-12.64 (s, 1H), 9.10 (s, 1H), 8.85 (t,J = 6.8 Hz, 2H), 8.68 (d, J = 8.6 Hz, 1H), 8.58 (d, J = 5.1 Hz, 1H),7.92 (d, J = 4.6 Hz, 1H), 7.78 (d, J = 7.5 Hz, 1H), 7.72- 7.63 (m, 2H),6.69 (d, J = 13.3 Hz, 1H), 6.65 (s, 1H), 4.84 (d, J = 8.6 Hz, 1H), 4.79(d, J = 11.1 Hz, 2H), 4.27 (d, J = 7.5 Hz, 2H), 4.14 (d, J = 12.7 Hz,1H), 3.95 (d, J = 11.1 Hz, 1H), 3.79-3.69 (m, 2H), 3.54 (t, J = 12.5 Hz,1H), 3.50-3.41 (m, 1H), 3.35 (d, J = 12.4 Hz, 1H), 3.25 (t, J = 12.3 Hz,1H), 2.03 (s, 3H), 1.30 (t, J = 7.2 Hz, 3H). 695.3 0.117 418

1H NMR (400 MHz, DMSO-d6) δ 12.94 (s, 1H), 8.87 (d, J = 7.9 Hz, 1H),8.84 (d, J = 4.2 Hz, 1H), 8.67 (d, J = 8.8 Hz, 1H), 8.07 (s, 2H), 7.93(s, 1H), 7.77 (d, J = 7.6 Hz, 1H), 7.68 (d, J = 7.1 Hz, 2H), 7.66 (s,1H), 6.73-6.63 (m, 2H), 4.90-4.72 (m, 3H), 4.15 (d, J = 12.6 Hz, 1H),3.95 (d, J = 11.3 Hz, 1H), 3.82-3.70 (m, 2H), 3.64 (s, 3H), 3.50 (dt, J= 33.6, 12.1 Hz, 3H), 3.35 (d, J = 13.4 Hz, 1H), 3.27 (d, J = 12.8 Hz,1H), 2.04 (s, 3H). 764.4 0.104 419

1H NMR (400 MHz, DMSO-d6) δ 9.27 (d, J = 8.1 Hz, 1H), 9.05 (s, 1H), 8.85(d, J = 3.8 Hz, 1H), 8.70 (d, J = 8.6 Hz, 1H), 8.60 (d, J = 5.0 Hz, 1H),7.91 (d, J = 5.2 Hz, 1H), 7.78 (d, J = 7.6 Hz, 1H), 7.72-7.63 (m, 3H),7.53-7.41 (m, 2H), 7.39 (s, 1H), 5.21 (dd, J = 13.7, 5.4 Hz, 2H), 4.88(s, 1H), 3.82 (d, J = 15.3 Hz, 1H), 3.66 (d, J = 2.9 Hz, 3H), 3.48 (dd,J = 14.7, 10.9 Hz, 1H), 2.14 (s, 3H). 676.2 0.369 420

1H NMR (400 MHz, DMSO-d6) δ 8.85 (t, J = 6.2 Hz, 2H), 8.68 (d, J = 5.8Hz, 2H), 7.76 (d, J = 7.5 Hz, 1H), 7.68 (dd, J = 8.2, 4.8 Hz, 3H),6.71-6.61 (m, 2H), 4.88-4.73 (m, 2H), 4.14 (d, J = 12.7 Hz, 1H),3.97-3.92 (m, 2H), 3.75 (m, 1H), 3.63 (d, J = 2.5 Hz, 3H), 3.56 (dd, J =13.0, 2.7 Hz, 1H), 3.46 (dd, J = 14.6, 10.8 Hz, 1H), 3.35 (d, J = 12.6Hz, 1H), 3.26 (d, J = 12.4 Hz, 1H), 2.02 (s, 3H). 699.1 0.116 421

1H NMR (400 MHz, DMSO-d6) δ 13.31-12.61 (s, 1H), 11.90 (d, J = 3.2 Hz,1H), 8.87 (d, J = 8.2 Hz, 2H), 8.72 (s, 1H), 8.68 (d, J = 8.8 Hz, 1H),8.48 (d, J = 5.1 Hz, 1H), 7.82 (s, 1H), 7.77 (d, J = 7.6 Hz, 1H), 7.68(d, J = 7.9 Hz, 2H), 6.69 (d, J = 13.3 Hz, 1H), 6.65 (s, 1H), 4.84 (d, J= 9.4 Hz, 1H), 4.77 (s, 1H), 4.14 (d, J = 12.7 Hz, 1H), 3.95 (d, J =11.4 Hz, 1H), 3.76 (d, J = 10.6 Hz, 2H), 3.54 (t, J = 12.0 Hz, 1H), 3.46(t, J = 12.8 Hz, 1H), 3.35 (d, J = 12.5 Hz, 1H), 3.25 (t, J = 12.2 Hz,1H), 2.04 (s, 3H). 667.2 0.191 422

1H NMR (400 MHz, DMSO-d6) δ 13.10-12.83, (s, 1H), 9.01 (d, J = 7.8 Hz,1H), 8.84 (d, J = 4.2 Hz, 1H), 8.65 (d, J = 8.7 Hz, 1H), 8.00 (t, J =9.1 Hz, 1H), 7.80 (dd, J = 12.1, 6.4 Hz, 1H), 7.73 (d, J = 7.6 Hz, 1H),7.65 (d, J = 7.5 Hz, 2H), 6.78 (d, J = 11.8 Hz, 2H), 4.92 (d, J = 9.8Hz, 1H), 4.70 (s, 1H), 4.16 (d, J = 12.8 Hz, 1H), 3.99-3.91 (m, 1H),3.74 (d, J = 13.7 Hz, 2H), 3.57 (s, 1H), 3.55 (s, 3H), 3.44 (d, J = 12.1Hz, 2H), 3.26 (d, J = 12.7 Hz, 1H). 720.1 0.231 423

1H NMR (400 MHz, DMSO-d6) δ 9.01 (d, J = 7.8 Hz, 1H), 8.87- 8.82 (m,1H), 8.67 (d, J = 8.6 Hz, 1H), 8.14-8.06 (m, 1H), 7.74 (d, J = 7.6 Hz,1H), 7.70-7.62 (m, 2H), 7.53-7.46 (m, 1H), 7.21 (t, J = 8.4 Hz, 1H),6.78 (d, J = 11.8 Hz, 2H), 4.96-4.86 (m, 1H), 4.76-4.65 (m, 1H), 4.16(d, J = 12.7 Hz, 1H), 4.00-3.90 (m, 1H), 3.78-3.70 (m, 2H), 3.62-3.39(m, 6H), 3.24 (t, J = 12.3 Hz, 1H). 702.2 0.08 424

1H NMR (400 MHz, DMSO-d6) δ 9.02 (d, J = 7.8 Hz, 1H), 8.90 (s, 1H), 8.84(d, J = 4.2 Hz, 1H), 8.68 (d, J = 8.6 Hz, 1H), 7.80- 7.72 (m, 2H), 7.67(t, J = 6.7 Hz, 2H), 6.78 (d, J = 11.8 Hz, 2H), 4.92 (dd, J = 10.0, 3.4Hz, 1H), 4.71 (s, 1H), 4.16 (d, J = 12.7 Hz, 1H), 4.01-3.90 (m, 1H),3.74 (d, J = 13.3 Hz, 2H), 3.63 (s, 3H), 3.50 (dt, J = 42.0, 12.4 Hz,3H), 3.24 (t, J = 12.3 Hz, 1H), 2.60 (s, 3H). 700.1 0.15 425

1H NMR (400 MHz, DMSO-d6) δ 8.93-8.81 (m, 3H), 8.68 (d, J = 8.6 Hz, 1H),7.81-7.71 (m, 2H), 7.67 (dd, J = 8.4, 4.2 Hz, 2H), 6.73-6.61 (m, 2H),4.91-4.71 (m, 2H), 4.14 (d, J = 12.6 Hz, 1H), 3.99-3.89 (m, 1H), 3.80-3.68 (m, 2H), 3.63 (t, J = 1.8 Hz, 3H), 3.50 (ddd, J = 33.4, 13.8, 10.0Hz, 2H), 3.35 (d, J = 12.3 Hz, 1H), 3.25 (t, J = 12.5 Hz, 1H), 2.60 (s,3H), 2.02 (s, 3H). 695.2 0.185 426

1H NMR (400 MHz, DMSO-d6) δ 9.04 (s, 1H), 8.90 (t, J = 1.8 Hz, 1H), 8.85(d, J = 8.1 Hz, 1H), 8.60 (d, J = 5.0 Hz, 1H), 8.51- 8.44 (m, 1H), 7.91(t, J = 3.9 Hz, 1H), 7.75 (d, J = 2.5 Hz, 2H), 6.82-6.68 (m, 3H), 6.65(d, J = 7.6 Hz, 2H), 4.97-4.73 (m, 4H), 4.15 (dd, J = 12.7, 7.7 Hz, 2H),4.03-3.87 (m, 3H), 3.84-3.68 (m, 1H), 3.65 (s, 3H), 3.59-3.40 (m, 2H),3.40-3.16 (m, 3H), 2.01 (s, 3H). 699.2 0.096 427

1H NMR (400 MHz, DMSO-d6) δ 9.10 (s, 1H), 8.91 (d, J = 2.5 Hz, 1H),8.88-8.83 (m, 2H), 8.49 (d, J = 10.3 Hz, 1H), 7.75 (d, J = 1.7 Hz, 2H),7.60 (d, J = 6.0 Hz, 1H), 6.73-6.60 (m, 2H), 4.81 (d, J = 11.0 Hz, 2H),4.14 (d, J = 12.5 Hz, 1H), 3.94 (d, J = 11.8 Hz, 1H), 3.72 (s, 1H), 3.68(d, J = 4.5 Hz, 1H), 3.60-3.42 (m, 5H), 3.35 (d, J = 12.4 Hz, 1H), 3.25(t, J = 12.1 Hz, 1H), 2.02 (d, J = 7.4 Hz, 3H). 699.2 0.355 428

1H NMR (400 MHz, DMSO-d6) δ 9.01 (d, J = 7.8 Hz, 1H), 8.85 (d, J = 4.2,1.4 Hz, 1H), 8.69 (d, J = 8.6 Hz, 1H), 8.61 (s, 1H), 7.76 (d, J = 7.5Hz, 1H), 7.71-7.64 (m, 2H), 7.29 (d, J = 2.3 Hz, 1H), 6.78 (d, J = 11.7Hz, 2H), 4.97- 4.86 (m, 1H), 4.76-4.67 (m, 1H), 4.16 (d, J = 12.7 Hz,1H), 3.99-3.91 (m, 4H), 3.75 (dd, J = 14.4, 4.4 Hz, 2H), 3.60 (s, 3H),3.58-3.39 (m, 3H), 3.25 (t, J = 11.2 Hz, 1H). 715.3 0.18 429

1H NMR (400 MHz, DMSO-d6) δ 8.88-8.84 (m, 2H), 8.70 (d, J = 8.6 Hz, 1H),8.62 (s, 1H), 7.76 (d, J = 7.5 Hz, 1H), 7.71-7.66 (m, 2H), 7.29 (d, J =3.4 Hz, 1H), 6.72-6.63 (m, 2H), 4.89-4.73 (m, 2H), 4.14 (d, J = 12.6 Hz,1H), 3.99-3.90 (m, 4H), 3.81- 3.69 (m, 2H), 3.60 (d, J = 2.5 Hz, 3H),3.58-3.41 (m, 2H), 3.35 (d, J = 10.6 Hz, 1H), 3.26 (d, J = 12.3 Hz, 1H),2.03 (s, 3H). 711.4 0.162 430

1H NMR (400 MHz, DMSO-d6) δ 9.09 (s, 1H), 9.01 (d, J = 7.9 Hz, 1H), 8.91(d, J = 2.5 Hz, 1H), 8.85 (d, J = 6.0 Hz, 1H), 8.54- 8.41 (m, 1H), 7.74(q, J = 7.8 Hz, 2H), 7.59 (d, J = 6.1 Hz, 1H), 6.77 (d, J = 11.8 Hz,2H), 4.98- 4.85 (m, 1H), 4.73 (tt, J = 9.3, 4.3 Hz, 1H), 4.16 (d, J =12.7 Hz, 1H), 3.95 (dd, J = 11.7, 3.7 Hz, 1H), 3.76 (s, 2H), 3.66 (m,1H), 3.57 (s, 3H), 3.43 (d, J = 14.8 Hz, 2H), 3.30-3.17 (m, 1H). 703.80.469 431

1H NMR (400 MHz, DMSO-d6) δ 8.87 (d, J = 8.1 Hz, 1H), 8.86- 8.83 (m,1H), 8.70-8.65 (m, 1H), 8.14-8.07 (m, 1H), 7.75- 7.72 (m, 1H), 7.70-7.64(m, 2H), 7.53-7.46 (m, 1H), 7.25- 7.17 (m, 1H), 6.72-6.63 (m, 2H),4.89-4.80 (m, 1H), 4.80- 4.72 (m, 1H), 4.14 (d, J = 12.6 Hz, 1H),3.97-3.91 (m, 1H), 3.80-3.69 (m, 2H), 3.61-3.53 (m, 3H), 3.53-3.42 (m,1H), 3.35 (d, J = 12.6 Hz, 1H), 3.26 (d, J = 15.6 Hz, 2H), 2.03 (s, 3H).698.2 0.094 432

1H NMR (400 MHz, DMSO-d6) δ 8.86 (d, J = 8.0 Hz, 3H), 8.68 (d, J = 8.4Hz, 1H), 8.42 (d, J = 9.3 Hz, 1H), 7.76 (d, J = 7.5 Hz, 1H), 7.70-7.63(m, 2H), 7.45-7.39 (m, 1H), 6.73-6.63 (m, 2H), 4.87-4.72 (m, 3H), 4.14(d, J = 12.6 Hz, 1H), 3.99-3.91 (m, 2H), 3.74 (s, 2H), 3.63 (s, 3H),3.58-3.51 (m, 1H), 3.50-3.42 (m, 1H), 3.38-3.31 (m, 1H), 3.28-3.21 (m,1H), 2.03 (s, 3H). 681.2 0.11 433

1H NMR (400 MHz, DMSO-d6) δ 9.07 (s, 1H), 8.88 (dd, J = 8.2, 3.2 Hz,2H), 8.69 (dd, J = 8.7, 1.5 Hz, 1H), 8.63 (dd, J = 5.0, 1.4 Hz, 1H),7.94 (t, J = 4.4 Hz, 1H), 7.69 (td, J = 9.8, 9.3, 3.4 Hz, 2H), 6.79-6.60(m, 2H), 4.81 (dtd, J = 12.0, 7.6, 3.7 Hz, 2H), 4.14 (d, J = 12.6 Hz,1H), 3.94 (dd, J = 11.5, 3.6 Hz, 1H), 3.83 (dd, J = 14.7, 3.9 Hz, 1H),3.77-3.64 (m, 4H), 3.64-3.41 (m, 2H), 3.35 (d, J = 12.3 Hz, 1H),3.31-3.18 (m, 1H), 2.04 (d, J = 7.5 Hz, 3H). 699.2 0.076 434

1H NMR (400 MHz, DMSO-d6) δ 9.10 (d, J = 3.6 Hz, 1H), 8.95- 8.76 (m,3H), 8.68 (d, J = 8.7 Hz, 1H), 7.76 (d, J = 7.5 Hz, 1H), 7.74-7.56 (m,3H), 6.74-6.56 (m, 2H), 4.90-4.72 (m, 2H), 4.14 (d, J = 12.6 Hz, 1H),3.94 (dd, J = 11.4, 3.6 Hz, 1H), 3.75 (t, J = 13.4 Hz, 2H), 3.57 (d, J =2.4 Hz, 3H), 3.55-3.48 (m, 1H), 3.47 (s, 1H), 3.35 (d, J = 12.6 Hz, 1H),3.25 (t, J = 12.4 Hz, 1H), 2.03 (s, 3H). 681.2 0.103 435

1H NMR (400 MHz, DMSO-d6) δ 9.23 (t, J = 9.0 Hz, 1H), 8.82 (dt, J = 4.0,1.9 Hz, 1H), 8.64 (d, J = 8.7 Hz, 1H), 7.69-7.55 (m, 3H), 7.42 (ddd, J =24.4, 15.8, 6.8 Hz, 4H), 6.55 (d, J = 2.9 Hz, 1H), 5.24-5.16 (m, 2H),4.90-4.80 1H), 3.86-3.70 (m, 1H), 3.49 (s, 2H), 3.51-3.32 (m, 2H), 2.53(s, 4H), 2.18 (t, J = 7.3 Hz, 2H), 2.10 (d, J = 3.5 Hz, 3H), 1.52-1.43(m, 3H), 0.85 (t, J = 6.6 Hz, 4H). 690.2 0.524 436

1H NMR (400 MHz, DMSO-d6) δ 9.05 (d, J = 2.1 Hz, 1H), 8.93- 8.80 (m,1H), 8.75 (d, J = 8.1 Hz, 1H), 8.68 (d, J = 8.6 Hz, 1H), 8.60 (d, J =5.0 Hz, 1H), 7.92 (dt, J = 5.3, 3.3 Hz, 1H), 7.76 (dd, J = 7.7, 2.2 Hz,1H), 7.73-7.61 (m, 2H), 6.39 (d, J = 7.7 Hz, 2H) 6.30 (d, J = 9.2 Hz,1H), 4.74 (d, J = 10.0 Hz, 1H), 4.18 (s, 2H), 3.75 (d, J = 16.7 Hz, 1H),3.66 (d, J = 2.6 Hz, 3H), 3.44 (dd, J = 14.6, 10.8 Hz, 1H), 1.98 (s,3H), 1.85-1.68 (m, 1H), 1.53 (dt, J = 15.8, 8.1 Hz, 1H), 1.01-0.87 (m,3H). 653.3 0.076 437

1H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 8.97 (d, J = 8.0 Hz, 1H),8.86 (dd, J = 4.2, 1.5 1H), 8.68 (dd, J = 8.8, 1.7 Hz, 1H), 7.69-7.56(m, 3H), 7.35 (s, 1H), 6.76 (d, J = 11.7 Hz, 2H), 4.98-4.85 (m, 1H),4.73-4.63 (m, 1H), 4.31 (d, J = 14.7 Hz, 1H), 4.21-4.06 (m, 2H), 3.96(dd, J = 11.5, 3.8 Hz, 1H), 3.81-3.66 (m, 3H), 3.61- 3.47 (m, 4H),3.47-3.36 (m, 3H), 3.31-3.06 (m, 3H), 2.97 (s, 3H). 686.3 0.261 438

1H NMR (400 MHz, DMSO-d6) δ 9.11 (s, 2H), 8.97 (d, J = 8.0 Hz, 1H),8.88-8.82 (m, 1H), 8.67 (d, J = 8.7 Hz, 1H), 7.69-7.55 (m, 3H), 7.37 (s,1H), 6.76 (d, J = 12.0 Hz, 2H), 4.96-4.86 (m, 1H), 4.73-4.63 (m, 1H),4.17 (d, J = 12.8 Hz, 1H), 4.09 (s, 2H), 3.96 (d, J = 11.6 Hz, 1H), 3.73(t, J = 12.0 Hz, 2H), 3.61- 3.52 (m, 1H), 3.51-3.46 (m, 4H), 3.46-3.37(m, 2H), 3.25 (t, J = 12.6 Hz, 1H), 3.10-3.02 (m, 2H). 672.3 0.291 439

1H NMR (400 MHz, DMSO-d6) δ 9.05 (d, J = 2.1 Hz, 1H), 8.93- 8.80 (m,1H), 8.75 (d, J = 8.1 Hz, 1H), 8.68 (d, J = 8.6 Hz, 1H), 8.60 (d, J =5.0 Hz, 1H), 7.92 (dt, J = 5.3, 3.3 Hz, 1H), 7.76 (dd, J = 7.7, 2.2 Hz,1H), 7.73-7.61 (m, 2H), 6.39 (d, J = 7.7 Hz, 2H), 6.30 (d, J = 9.2 Hz,1H), 4.74 (d, J = 10.0 Hz, 1H), 4.18 (s, 2H), 3.75 (d, J = 16.7 Hz, 1H),3.66 (d, J = 2.6 Hz, 3H), 3.44 (dd, J = 14.6, 10.8 Hz, 1H), 1.98 (s,3H), 1.85-1.68 (m, 1H), 1.53 (dt, J = 15.8, 8.1 Hz, 1H), 1.01-0.87 (m,3H). 653.3 0.049 440

1H NMR (400 MHz, DMSO-d6) δ 13.18-12.55 (s, 1H), 8.94 (s, 1H), 8.87 (s,1H), 8.72 (s, 1H), 7.64 (dd, J = 18.1, 9.8 Hz, 2H), 7.56 (d, J = 8.1 Hz,1H), 6.74 (d, J = 12.2 Hz, 2H), 4.90 (d, J = 9.7 Hz, 1H), 4.72 (s, 1H),4.16 (d, J = 12.7 Hz, 1H), 3.95 (d, J = 11.5 Hz, 1H), 3.81 (s, 1H), 3.71(t, J = 14.1 Hz, 2H), 3.55 (t, J = 11.9 Hz, 1H), 3.48 (s, 3H), 3.45-3.33 (m, 1H), 3.25 (d, J = 12.7 Hz, 1H), 2.62 (d, J = 2.6 Hz, 3H), 1.86(d, J = 10.0 Hz, 3H). 646.3 0.25 441

1H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J = 4.2 Hz, 1H), 8.76 (dd, J = 7.8,2.7 Hz, 1H), 8.69 (d, J = 7.9 Hz, 1H), 7.66 (dd, J = 8.6, 4.3 Hz, 1H),7.60 (t, J = 7.3 Hz, 1H), 7.46 (d, J = 7.3 Hz, 1H), 6.56 (s, 1H), 6.42(dd, J = 11.9, 4.3 Hz, 2H), 4.69 (tt, J = 9.9, 5.6 Hz, 1H), 3.77-3.62(m, 3H), 3.56 (dt, J = 11.9, 5.6 Hz, 6H), 3.49 (s, 4H), 2.54 (s, 3H),1.84 (p, J = 5.9 Hz, 2H). 645.2 0.412 442

1H NMR (400 MHz, DMSO-d6) δ 8.90-8.82 (m, 1H), 8.73-8.63 (m, 2H),7.73-7.58 (m, 2H), 7.58-7.50 (m, 1H), 6.41-6.32 (m, 2H), 6.28 (d, J =9.2 Hz, 1H), 4.80-4.68 (m, 1H), 4.25-4.11 (m, 1H), 3.87-3.72 (m, 1H),3.51-3.44 (m, 3H), 3.38-3.27 1H), 2.60 (s, 3H), 1.92 (s, 3H), 1.89-1.79(m, 3H), 1.81- 1.67 (m, 1H), 1.60-1.46 (m, 1H), 0.92 (t, J = 7.3 Hz,3H). 614.3 0.227 443

1H NMR (400 MHz, DMSO-d6) δ 9.44 (t, J = 8.3 Hz, 1H), 9.36- 9.27 (m,1H), 8.81 (d, J = 8.4 Hz, 1H), 8.18-8.11 (m, 1H), 7.96 (d, J = 7.3 Hz,1H), 6.63 (t, J = 5.8 Hz, 2H), 4.86-4.76 (m, 3H), 4.14 (d, J = 12.7 Hz,1H), 3.95- 3.86 (m, 3H), 3.72 (m, 1H), 3.53 (d, J = 11.5 Hz, 2H), 3.32(d, J = 12.1 Hz, 1H), 3.24 (d, J = 9.8 Hz, 1H), 2.69 (s, 6H), 2.36 (s,3H), 2.01 (s, 3H). 626.2 0.714 444

1H NMR (400 MHz, DMSO-d6) δ 8.93 (s, 1H), 8.91-8.78 (m, 2H), 7.77 (s,1H), 7.72-7.62 (m, 2H), 7.40 (d, J = 7.0 Hz, 1H), 6.72- 6.61 (m, 2H),6.31 (d, J = 7.1 Hz, 1H), 4.89-4.70 (m, 1H), 4.14 (d, J = 12.6 Hz, 1H),3.94 (dd, J = 11.2, 3.6 Hz, 1H), 3.81-3.69 (m, 2H), 3.50 (s, 4H),3.47-3.18 (m, 3H), 2.46 (s, 3H), 2.00 (s, 3H). 627.1 0.161 445

1H NMR (400 MHz, DMSO-d6) δ 8.93-8.77 (m, 2H), 8.65 (s, 1H), 7.74-7.52(m, 2H), 7.43 (dd, J = 7.4, 3.3 Hz, 1H), 6.69-6.48 (m, 3H), 4.75-4.59(m, 1H), 3.77-3.56 (m, 3H), 3.55-3.33 (m, 4H), 3.19 (d, J = 7.1 Hz, 2H),3.17-3.03 (m, 2H), 2.53 (s, 3H), 1.66 (dq, J = 14.8, 7.4 Hz, 1H), 1.40(dq, J = 14.6, 7.4 Hz, 1H), 1.09 (s, 3H), 0.83 (t, J = 7.5 Hz, 3H).673.2 0.984 446

1H NMR (400 MHz, DMSO-d6) δ 12.92 (s, 1H), 8.80 (t, J = 5.3 Hz, 1H),8.68 (d, J = 8.3 Hz, 1H), 8.61 (d, J = 8.4 Hz, 1H), 7.67- 7.54 (m, 2H),7.42 (dd, J = 11.0, 7.2 Hz, 1H), 6.59 (d, J = 11.2 Hz, 2H), 6.54 (d, J =5.6 Hz, 1H), 4.90 (s, 1H), 4.84-4.63 (m, 2H), 4.12 (d, J = 13.4 Hz, 1H),3.92 (d, J = 11.3 Hz, 2H), 3.80 (d, J = 15.7 Hz, 1H), 3.71 (d, J = 15.7Hz, 1H), 3.70 (m, 1H), 3.49 (d, J = 3.6 Hz, 3H), 3.31 (d, J = 11.7 Hz,1H), 3.26 (s, 3H), 1.93 (d, J = 6.7 Hz, 6H). 691.2 0.318 447

1H NMR (400 MHz, DMSO-d6) δ 8.94 (d, J = 7.8 Hz, 1H), 8.84- 8.77 (m,1H), 8.68-8.59 (m, 1H), 7.66-7.53 (m, 2H), 7.43 (dd, J = 7.4, 4.0 Hz,1H), 6.76 (dd, J = 11.5, 4.1 Hz, 2H), 6.54 (s, 1H), 4.75-4.65 (m, 1H),4.38- 4.24 (m, 1H), 4.09-4.01 (m, 1H), 3.92-3.85 (m, 1H), 3.78- 3.62 (m,3H), 3.53-3.37 (m, 4H), 2.92-2.77 (m, 2H), 2.53 (s, 3H). 699.2 0.271 448

1H NMR (400 MHz, DMSO-d6) δ 13.07-12.69 (s, 1H), 8.87 (d, J = 4.1 Hz,1H), 8.81 (d, J = 8.2 Hz, 1H), 8.68 (d, J = 8.6 Hz, 1H), 7.69 (d, J =7.4 Hz, 1H), 7.67- 7.63 (m, 1H), 7.60 (m, 2H), 6.66 (d, J = 16.6 Hz,2H), 4.83 (d, J = 9.5 Hz, 1H), 4.76 (d, J = 11.4 Hz, 1H), 4.14 (d, J =12.6 Hz, 1H), 3.94 (d, J = 11.5 Hz, 1H), 3.73 (d, J = 13.3 Hz, 2H), 3.60(s, 3H), 3.54 (dd, J = 13.7, 10.4 Hz, 1H), 3.44-3.38 (m, 1H), 3.35 (d, J= 16.3 Hz, 1H), 3.26 (d, J = 12.4 Hz, 1H), 2.60 (s, 3H), 2.00 (s, 3H).695.1 0.307 449

1H NMR (400 MHz, DMSO-d6) δ 8.88 (d, J = 3.5 Hz, 1H), 8.83 (t, J = 7.6Hz, 1H), 8.75 (d, J = 8.6 Hz, 1H), 7.74-7.68 (m, 1H), 7.65 (t, J = 6.8Hz, 1H), 7.55 (dd, J = 7.3, 4.5 Hz, 1H), 6.70-6.61 (m, 2H), 6.49 (d, J =4.1 Hz, 1H), 4.79 (dtd, J = 19.1, 11.2, 9.8, 5.4 Hz, 2H), 4.14 (d, J =12.6 Hz, 1H), 3.94 (dd, J = 11.5, 3.6 Hz, 1H), 3.81-3.69 (m, 4H), 3.45(d, J = 3.3 Hz, 3H), 3.40-3.32 (m, 1H), 3.24 (t, J = 12.5 Hz, 1H), 2.46(s, 3H), 1.98 (d, J = 6.2 Hz, 3H). 661.1 0.092 450

1H NMR (400 MHz, DMSO-d6) δ 8.95 (d, J = 4.5 Hz, 1H), 8.89 (d, J = 8.1Hz, 1H), 8.83 (d, J = 8.1 Hz, 1H), 7.82-7.72 (m, 2H), 7.68 (d, J = 8.0Hz, 2H), 6.67 (d, J = 13.0 Hz, 2H), 4.82 (dt, J = 10.8, 5.4 Hz, 1H),4.79-4.70 1H), 4.15 (d, J = 12.6 Hz, 1H), 3.98-3.92 (m, 2H), 3.75 (s,1H), 3.53 (s, 4H), 3.44 (dd, J = 14.6, 10.2 Hz, 1H), 3.34 (d, J = 12.1Hz, 1H), 3.29-3.20 (m, 1H), 2.66 (s, 6H), 2.53 (s, 4H), 2.03 (s, 3H).670.3 1.02 451

1H NMR (400 MHz, DMSO-d6) δ 8.90 (t, J = 4.3 Hz, 1H), 8.87- 8.78 (m,2H), 8.12 (d, J = 1.9 Hz, 1H), 7.81-7.65 (m, 2H), 7.57 (t, J = 7.8 Hz,1H), 6.70-6.60 (m, 2H), 4.88-4.73 (m, 2H), 4.14 (d, J = 12.6 Hz, 1H),3.94 (dd, J = 11.6, 3.7 Hz, 1H), 3.84 (dd, J = 14.4, 3.9 Hz, 1H),3.76-3.66 (m, 2H), 3.58-3.48 (m, 1H), 3.45 (d, J = 2.8 Hz, 3H), 3.41-3.29 (m, 1H), 3.29-3.18 (m, 1H), 1.98 (d, J = 3.5 Hz, 3H), 1.82 (d, J =12.7 Hz, 3H). 661.1 0.208 452

1H NMR (400 MHz, DMSO-d6) δ 8.86 (d, J = 2.7 Hz, 1H), 8.81 (d, J = 8.1Hz, 1H), 8.40 (dd, J = 10.7, 2.8 Hz, 1H), 7.64 (d, J = 7.4 Hz, 1H), 7.56(d, J = 7.3 Hz, 1H), 6.67 (d, J = 14.5 Hz, 2H), 4.87-4.79 (m, 1H), 4.73(ddd, J = 10.1, 8.1, 4.4 Hz, 1H), 4.14 (d, J = 12.6 Hz, 1H), 3.94 (dd, J= 11.5, 3.6 Hz, 1H), 3.73 (dt, J = 12.0, 2.9 Hz, 1H), 3.65 (dd, J =14.6, 4.4 Hz, 1H), 3.55 (dd, J = 12.0, 3.5 Hz, 1H), 3.51 (s, 3H), 3.42(dd, J = 14.6, 10.0 Hz, 1H), 3.35 (d, J = 12.2 Hz, 1H), 3.25 (t, J =12.2 Hz, 1H), 2.40 (s, 3H), 2.31 (s, 3H), 2.06 (d, J = 8.9 Hz, 3H).660.2 0.232 453

1H NMR (400 MHz, DMSO-d6) δ 8.88 (d, J = 4.2 Hz, 1H), 8.82- 8.70 (m,2H), 7.77-7.66 (m, 2H), 7.64 (d, J = 7.3 Hz, 1H), 6.69-6.60 (m, 2H),4.90-4.77 (m, 1H), 4.77-4.66 (m, 1H), 3.74 (dd, J = 14.3, 4.3 Hz, 1H),3.59-3.48 (m, 4H), 3.44 (dd, J = 14.5, 10.2 Hz, 1H), 3.03 (t, J = 12.0Hz, 1H), 2.42 (s, 3H), 2.33 (s, 3H), 2.05 (s, 3H), 1.99-1.89 (m, 1H),1.86-1.67 (m, 2H), 1.67-1.41 (m, 3H). 640.2 0.677 454

1H NMR (400 MHz, DMSO-d6) δ 9.09 (d, J = 8.1 Hz, 1H), 8.92- 8.83 (m,1H), 8.78-8.67 (m, 1H), 7.77-7.58 (m, 3H), 6.95- 6.85 (m, 2H), 4.98-4.86(m, 1H), 4.80-4.69 (m, 1H), 4.15 (d, J = 12.6 Hz, 1H), 3.99-3.91 1H),3.77-3.69 (m, 2H), 3.52 (s, 3H), 3.42-3.35 (m, 2H), 3.30-3.15 (m, 2H),2.41 (s, 3H), 2.33 (s, 3H). 663.2 0.14 455

1H NMR (400 MHz, DMSO-d6) δ 8.93 (dd, J = 17.1, 6.7 Hz, 2H), 8.81 (d, J= 8.2 Hz, 1H), 7.95- 7.54 (m, 3H), 7.38 (s, 1H), 6.66 (d, J = 13.4 Hz,2H), 4.86-4.73 (m, 2H), 4.14 (d, J = 12.7 Hz, 1H), 3.94 (dd, J = 11.4,3.6 Hz, 1H), 3.78-3.67 (m, 2H), 3.57 (d, J = 3.2 Hz, 3H), 3.51-3.16 (m,4H), 2.40 (s, 3H), 2.15 (s, 3H), 2.01 (s, 3H). 641.2 0.211 456

1H NMR (400 MHz, DMSO-d6) δ 8.98 (d, J = 8.0 Hz, 1H), 8.91 (s, 1H), 8.78(s, 1H), 7.75 (d, J = 18.6 Hz, 2H), 7.63 (d, J = 7.4 Hz, 1H), 6.83 (dd,J = 12.3, 6.4 Hz, 1H), 6.71 (d, J = 9.3 Hz, 1H), 4.68 (dd, J = 9.0, 4.8Hz, 1H), 4.38-4.36 (m, 1H), 3.75 (dd, J = 14.5, 4.5 Hz, 1H), 3.53 (s,3H), 3.44 (dd, J = 14.5, 9.9 Hz, 1H), 2.42 (s, 3H), 2.34 (s, 3H), 1.83-1.70 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H). 636.2 0.248 457

1H NMR (400 MHz, DMSO-d6) δ 13.07-12.67 (s, 1H), 8.85 (s, 1H), 8.81 (dd,J = 8.3, 5.2 Hz, 1H), 8.69 (s, 1H), 8.38 (s, 1H), 7.75- 7.59 (s, 2H),7.56-7.47 (s, 1H), 6.71-6.57 (m, 2H), 4.83 (s, 1H), 4.80 (s, 2H), 4.14(d, J = 12.6 Hz, 1H), 3.94 (d, J = 10.2 Hz, 1H), 3.82 (d, J = 14.7 Hz,1H), 3.70 (t, J = 14.2 Hz, 1H), 3.56 (s, 1H), 3.51 (d, J = 2.7 Hz, 3H),3.33 (d, J = 11.6 Hz, 1H), 3.25 (d, J = 13.0 Hz, 1H), 1.97 (s, 3H), 1.83(d, J = 12.7 Hz, 3H). 695.2 0.238 458

1H NMR (400 MHz, DMSO-d6) δ 13.24-12.52 (s, 1H), 8.88-8.77 (m, 2H),8.67-8.59 (m, 1H), 7.62 (ddd, J = 17.7, 8.6, 5.0 Hz, 2H), 7.49 (t, J =6.9 Hz, 1H), 6.72-6.59 (m, 2H), 4.83 (d, J = 12.2 Hz, 1H), 4.80-4.70 (m,1H), 4.14 (d, J = 12.6 Hz, 1H), 3.94 (dd, J = 11.9, 3.6 Hz, 1H), 3.73(q, J = 12.6, 11.1 Hz, 2H), 3.53 (d, J = 4.4 Hz, 1H), 3.51 (d, J = 3.3Hz, 3H), 3.49-3.38 (m, 1H), 3.34 (d, J = 12.1 Hz, 1H), 3.26 (d, J = 12.5Hz, 1H), 2.66 (s, 3H), 1.96 (s, 3H). 696.2 0.09 459

1H NMR (400 MHz, DMSO-d6) δ 8.90 (d, J = 7.9 Hz, 1H), 8.84 (s, 1H), 8.69(s, 1H), 7.73-7.55 (m, 2H), 7.46 (s, 1H), 6.73 (dd, J = 11.5, 4.1 Hz,2H), 6.56 (s, 1H), 4.70 (d, J = 11.3 Hz, 1H), 4.45 (d, J = 6.8 Hz, 2H),4.41 (d, J = 6.3 Hz, 2H), 3.82-3.61 (m, 3H), 3.57-3.34 (m, 6H), 3.15 (t,J = 5.0 Hz, 2H), 2.54 (s, 3H). 673.2 2.066 460

1H NMR (400 MHz, DMSO-d6) δ 13.31-12.56 (s, 1H), 8.88 (s, 1H), 8.81 (dd,J = 8.3, 6.2 Hz, 1H), 8.75 (s, 1H), 7.67 (dd, J = 17.8, 10.3 Hz, 1H),7.58 (d, J = 6.9 Hz, 1H), 6.67 (s, 1H), 6.66-6.59 (m, 2H), 4.88-4.73 (m,2H), 4.14 (d, J = 12.6 Hz, 1H), 3.98-3.90 1H), 3.81 (d, J = 12.8 Hz,1H), 3.72 (d, J = 13.4 Hz, 2H), 3.53 (dd, J = 12.1, 8.6 Hz, 1H), 3.49(d, J = 3.3 Hz, 3H), 3.34 (d, J = 14.5 Hz, 1H), 3.24 (t, J = 12.4 Hz,1H), 2.63 (s, 3H), 1.96 (d, J = 8.2 Hz, 3H), 1.92 (s, 3H). 642.2 0.15461

1H NMR (400 MHz, DMSO-d6) δ 8.93-8.75 (m, 2H), 8.61 (d, J = 8.7 Hz, 1H),7.68-7.56 (m, 2H), 7.42 (t, J = 7.2 Hz, 1H), 6.72- 6.61 (m, 2H), 6.54(d, J = 3.1 Hz, 1H), 4.86-4.68 (m, 2H), 4.14 (d, J = 12.5 Hz, 1H), 3.94(d, J = 11.1 Hz, 1H), 3.65 (m, 3H), 3.49 (d, J = 3.3 Hz, 4H), 3.30 (dd,J = 33.7, 11.9 Hz, 3H), 2.53 (s, 3H), 1.98 (d, J = 3.0 Hz, 3H). 695.20.093 462

1H NMR (400 MHz, DMSO-d6) δ 8.88-8.77 (m, 2H), 8.66 (d, J = 8.7 Hz, 1H),7.70-7.56 (m, 2H), 7.45 (t, J = 7.2 Hz, 1H), 6.71- 6.60 (m, 2H), 6.55(d, J = 3.3 Hz, 1H), 4.89-4.69 (m, 2H), 4.14 (d, J = 12.6 Hz, 1H),3.99-3.89 (m, 1H), 3.81-3.73 (m, 2H), 3.55-3.42 (m, 4H), 3.41-3.30 (m,1H), 3.30-3.17 (m, 1H), 2.53 (s, 3H). 698.1 0.102 463

1H NMR (400 MHz, DMSO-d6) δ 8.95 (dd, J = 8.0, 2.7 Hz, 1H), 8.84 (dd, J= 4.3, 1.5 Hz, 1H), 8.74-8.65 (m, 1H), 7.70-7.64 (m, 1H), 7.62 (dd, J =7.5, 1.7 Hz, 1H), 7.45 (d, J = 7.3 Hz, 1H), 6.62 (ddd, J = 12.8, 4.2,2.2 Hz, 1H), 6.57-6.53 (m, 1H), 6.18 (dd, J = 13.7, 2.2 Hz, 1H), 4.93-4.71 (m, 2H), 4.13 (d, J = 12.6 Hz, 1H), 3.93 (dd, J = 11.5, 3.6 Hz,1H), 3.77-3.66 (m, 2H), 3.58-3.39 (m, 5H), 3.35-3.17 (m, 3H), 2.54 (s,3H), 1.87-1.68 (m, 1H), 0.71 (dd, J = 8.2, 3.5 Hz, 2H), 0.65-0.51 (m,1H). 721.2 0.205 464

1H NMR (400 MHz, DMSO-d6) δ 9.16 (d, J = 8.4 Hz, 1H), 8.88- 8.82 (m,2H), 8.80 (d, J = 6.5 Hz, 1H), 8.67 (dd, J = 8.7, 1.7 Hz, 1H), 8.22 (s,1H), 7.90-7.81 (m, 1H), 7.70-7.52 (m, 2H), 6.73- 6.62 (m, 2H), 4.90-4.72(m, 2H), 4.14 (d, J = 12.6 Hz, 1H), 3.98-3.92 (m, 1H), 3.85 (d, J = 14.3Hz, 1H), 3.80 (d, J = 4.2 Hz, 1H), 3.74 (s, 3H), 3.54 (dd, J = 13.7,10.4 Hz, 1H), 3.48-3.40 (m, 1H), 3.40-3.31 (m, 1H), 3.26 (d, J = 12.5Hz, 1H), 2.04 (d, J = 6.4 Hz, 3H). 682.1 0.13 465

1H NMR (400 MHz, DMSO-d6) δ 8.86-8.77 (m, 2H), 8.69-8.56 (m, 2H), 7.62(dd, J = 8.6, 4.2 Hz, 1H), 7.56 (d, J = 10.2 Hz, 1H), 6.75-6.62 (m, 2H),4.83 (dd, J = 8.9, 3.4 Hz, 1H), 4.75 (ddd, J = 11.7, 8.1, 3.9 Hz, 1H)4.14 (d, J = 12.6 Hz, 1H), 3.95 (s, 1H), 3.75 (s, 1H), 3.71 (s, 1H),3.54 (td, J = 11.6, 3.3 Hz, 1H), 3.43 (dd, J = 14.5, 10.8 Hz, 1H), 3.35(d, J = 11.8 Hz, 1H), 3.24 (t, J = 12.4 Hz, 1H), 2.49 (s, 3H), 2.34 (s,3H), 2.07 (s, 3H). 630.1 1.527 466

1H NMR (400 MHz, DMSO-d6) δ 8.87-8.72 (m, 2H), 8.64 (d, J = 8.6 Hz, 1H),7.69-7.54 (m, 2H), 7.44 (t, J = 6.9 Hz, 1H), 6.58- 6.44 (m, 3H), 4.75(dd, J = 19.5, 9.1 Hz, 1H), 3.81-3.56 (m, 3H), 3.56-3.25 (m, 4H), 3.19(s, 2H), 3.12 (s, 1H), 2.53 (s, 3H), 1.97 (s, 3H), 0.66 (d, J = 38.0 Hz,4H). 653.2 0.581 467

1H NMR (400 MHz, DMSO-d6) δ 13.14-12.59 (s, 1H), 8.89 (dd, J = 4.4, 1.4Hz, 1H), 8.81 (d, J = 8.2 Hz, 1H), 8.70 (d, J = 8.6 Hz, 1H), 7.93 (s,1H), 7.69 (d, J = 7.4 Hz, 2H), 7.61 (d, J = 7.4 Hz, 1H), 6.74-6.55 (m,2H), 4.83 (d, J = 7.2 Hz, 1H), 4.78-4.70 (m, 1H), 4.14 (d, J = 12.6 Hz,1H), 3.94 (dd, J = 11.5, 3.7 Hz, 1H), 3.78- 3.68 (m, 2H), 3.54 (s, 4H),3.41 (dd, J = 14.5, 10.5 Hz, 1H), 3.34 (d, J = 12.0 Hz, 1H), 3.24 (t, J= 12.1 Hz, 1H), 2.63 (s, 3H), 1.99 (s, 3H). 628.2 0.238 468

1H NMR (400 MHz, DMSO-d6) δ 12.90 (s, 1H), 8.95 (d, J = 8.1 Hz, 1H),8.80 (d, J = 5.1 Hz, 1H), 8.62 (s, 1H), 7.65-7.52 (m, 2H), 7.43 (d, J =5.8 Hz, 1H), 6.79 (dd, J = 11.5, 4.4 Hz, 2H), 6.54 (s, 1H), 4.69 (t, J =8.4 Hz, 2H), 4.29 (q, J = 6.7 Hz, 1H), 3.91- 3.81 (m, 1H), 3.73 (d, J =14.7 Hz, 1H), 3.65 (dd, J = 11.9, 4.3 Hz, 1H), 3.49 (d, J = 2.2 Hz, 3H),3.46 (s, 1H), 3.38 (d, J = 14.3 Hz, 1H), 3.23 (t, J = 12.5 Hz, 1H), 2.53(s, 3H), 1.37 (d, J = 6.6 Hz, 3H). 713.3 0.189 469

1H NMR (400 MHz, DMSO-d6) δ 9.20 (s, 1H), 8.88-8.84 (m, 1H), 8.83-8.78(m, 1H), 8.69 (dd, J = 8.7, 1.7 Hz, 1H), 8.19 (s, 1H), 7.90 (d, J = 6.7Hz, 1H), 7.72 (d, J = 7.3 Hz, 1H), 7.70-7.62 (m, 2H), 6.71-6.61 (m, 2H),4.92- 4.70 (m, 2H), 4.15 (d, J = 12.6 Hz, 1H), 3.95 (dd, J = 11.2, 3.6Hz, 1H), 3.78 (d, J = 4.2 Hz, 1H), 3.74 (s, 4H), 3.60-3.50 (m, 1H), 3.43(dd, J = 14.5, 10.5 Hz, 1H), 3.34 (d, J = 12.3 Hz, 1H), 3.25 (t, J =12.4 Hz, 1H), 2.02 (s, 3H). 664.4 0.103 470

1H NMR (400 MHz, DMSO-d6) δ 8.92 (dd, J = 8.0, 4.6 Hz, 1H), 8.84 (d, J =4.2 Hz, 1H), 8.68 (d, J = 8.6 Hz, 1H), 7.73-7.55 (m, 2H), 7.46 (d, J =7.3 Hz, 1H), 6.71 (d, J = 6.4 Hz, 1H), 6.64 (d, J = 13.0 Hz, 1H), 6.56(d, J = 2.7 Hz, 1H), 4.91 (d, J = 9.3 Hz, 1H), 4.74 (q, J = 12.2, 10.6Hz, 1H), 4.15 (d, J = 12.6 Hz, 1H), 3.95 (d, J = 10.8 Hz, 1H), 3.72 (t,J = 14.4 Hz, 2H), 3.55 (t, J = 11.2 Hz, 1H), 3.49 (d, J = 3.1 Hz, 3H),3.46-3.17 (m, 2H), 2.84 (dq, J = 13.7, 6.7 Hz, 1H), 2.54 (s, 3H), 1.05(dt, J = 11.2, 5.8 Hz, 6H). 723.2 0.181 471

1H NMR (400 MHz, DMSO-d6) δ 8.85 (dd, J = 12.2, 6.2 Hz, 2H), 8.68 (d, J= 8.7 Hz, 1H), 7.73- 7.55 (m, 2H), 7.46 (d, J = 7.0 Hz, 1H), 6.66 (d, J= 11.4 Hz, 2H), 6.56 (s, 1H), 4.94-4.66 (m, 2H), 4.14 (d, J = 12.6 Hz,1H), 3.95 (d, J = 11.3 Hz, 1H), 3.72 (t, J = 14.9 Hz, 2H), 3.63-3.31 (m,5H), 3.27 (d, J = 12.4 Hz, 1H), 2.54 (s, 3H), 2.39 (q, J = 7.5 Hz, 2H),1.06-0.90 (m, 3H). 709.2 0.179 472

1H NMR (400 MHz, DMSO-d6) δ 8.94 (d, J = 7.8 Hz, 1H), 8.83 (s, 1H), 8.68(s, 1H), 7.78-7.54 (m, 3H), 7.48 (t, J = 9.3 Hz, 2H), 7.34 (dq, J =16.4, 7.8 Hz, 3H), 6.82 (dd, J = 12.1, 3.7 Hz, 2H), 6.56 (d, J = 5.4 Hz,1H), 6.00 (q, J = 7.9 Hz, 1H), 4.71 (s, 1H), 3.71 (dt, J = 12.2, 5.8 Hz,2H), 3.49 (s, 4H), 3.01 (t, J = 6.4 Hz, 2H), 2.54 (s, 3H). 745.2 0.331473

1H NMR (400 MHz, DMSO-d6) δ 9.12 (t, J = 1.7 Hz, 1H), 9.02 (d, J = 7.8Hz, 1H), 8.86 (t, J = 4.7 Hz, 2H), 8.69 (d, J = 8.6 Hz, 1H), 7.77 (d, J= 7.5 Hz, 1H), 7.71- 7.47 (m, 3H), 6.78 (d, J = 11.7 Hz, 2H), 4.91 (dd,J = 8.8, 3.6 Hz, 1H), 4.71 (dt, J = 8.6, 4.6 Hz, 1H), 4.16 (d, J = 12.7Hz, 1H), 3.96 (dd, J = 11.6, 3.7 Hz, 1H), 3.86-3.70 (m, 3H), 3.62-3.38(m, 7H), 3.35-3.14 (m, 1H). 685.4 0.196 474

1H NMR (400 MHz, DMSO-d6) δ 13.24-12.63 (bs, 1H), 9.05 (s, 1H), 9.02 (d,J = 7.9 Hz, 1H), 8.84 (d, J = 4.1 Hz, 1H), 8.68 (d, J = 8.7 Hz, 1H),8.60 (d, J = 5.1 Hz, 1H), 7.91 (dd, J = 5.0, 2.3 Hz, 1H), 7.76 (dd, J =7.6, 1.8 Hz, 1H), 7.67 (d, J = 7.6 Hz, 2H), 6.78 (d, J = 11.9 Hz, 2H),4.91 (d, J = 9.9 Hz, 1H), 4.71 (s, 1H), 4.16 (d, J = 12.7 Hz, 1H), 4.00-3.92 (m, 1H), 3.74 (d, J = 13.0 Hz, 2H), 3.65 (s, 3H), 3.61- 3.40 (m,3H), 3.26 (d, J = 12.4 Hz, 1H). 685.3 0.112 475

1H NMR (400 MHz, DMSO-d6) δ 9.05 (s, 1H), 9.02 (d, J = 7.9 Hz, 1H), 8.85(d, J = 4.2 Hz, 1H), 8.68 (d, J = 8.6 Hz, 1H), 8.60 (d, J = 5.0 Hz, 1H),7.95-7.86 (m, 1H), 7.76 (d, J = 7.5 Hz, 1H), 7.68 (t, J = 6.5 Hz, 2H),6.80 (dd, J = 17.6, 12.4 Hz, 5H), 4.93 (ddt, J = 17.8, 8.9, 4.6 Hz, 2H),4.78- 4.55 (m, 1H), 4.17 (dd, J = 12.8, 4.3 Hz, 3H), 4.00-3.91 (m, 3H),3.75 (dd, J = 14.4, 4.2 Hz, 4H), 3.65 (s, 3H), 3.54 (td, J = 14.7, 13.3,9.5 Hz, 4H), 3.44 (d, J = 15.1 Hz, 1H), 3.31-3.14 (m, 2H). 657.2 0.157476

1H NMR (400 MHz, DMSO-d6) δ 9.12 (dd, J = 18.2, 8.5 Hz, 1H), 9.02 (d, J= 4.8 Hz, 1H), 8.92 (dd, J = 10.8, 8.3 Hz, 1H), 7.93 (dt, J = 32.7, 6.7Hz, 1H), 7.82- 7.55 (m, 2H), 6.70 (dd, J = 14.9, 11.7 Hz, 2H), 5.84 (d,J = 6.9 Hz, 1H), 4.97-4.84 (m, 1H), 4.83- 4.69 (m, 1H), 4.15 (dd, J =12.8, 3.1 Hz, 1H), 3.94 (dd, J = 9.7, 5.7 Hz, 2H), 3.66 (ddt, J = 51.3,42.1, 11.8 Hz, 7H), 3.37 (d, J = 6.2 Hz, 4H), 3.26 (d, J = 26.6 Hz, 2H),2.41 (d, J = 2.9 Hz, 3H). 722.3 0.337 477

1H NMR (400 MHz, DMSO-d6) δ 8.88 (d, J = 4.2 Hz, 1H), 8.82 (d, J = 8.1Hz, 1H), 8.74 (d, J = 8.6 Hz, 1H), 7.71 (s, 2H), 7.64 (d, J = 7.4 Hz,1H), 6.67 (d, J = 14.4 Hz, 2H), 4.83 (d, J = 9.6 Hz, 1H), 4.78-4.70 (m,1H), 4.14 (s, 1H), 3.93 (s, 1H), 3.73 (s, 1H), 3.55 (d, J = 9.6 Hz, 4H),3.44 (dd, J = 14.5, 10.2 Hz, 2H), 3.33 (s, 1H), 3.26 (d, J = 12.4 Hz,1H), 2.41 (s, 3H), 2.33 (s, 3H), 2.05 (s, 3H). 642.2 0.115 478

1H NMR (400 MHz, DMSO-d6) δ 9.02 (d, J = 7.8 Hz, 1H), 8.83 (d, J = 4.2Hz, 1H), 8.68 (d, J = 8.6 Hz, 1H), 7.78-7.61 (m, 3H), 7.46 (d, J = 9.2Hz, 1H), 7.39 (dd, J = 9.2, 3.0 Hz, 1H), 7.28 (t, J = 2.9 Hz, 1H), 6.78(d, J = 11.7 Hz, 2H), 4.91 (dd, J = 9.0, 3.7 Hz, 1H), 4.71 (td, J = 8.7,4.3 Hz, 1H), 4.16 (d, J = 12.7 Hz, 1H), 3.95 (dd, J = 11.5, 3.8 Hz, 1H),3.76 (d, J = 3.2 Hz, 2H), 3.53 (s, 4H), 3.46 (dd, J = 19.1, 8.8 Hz, 2H),3.24 (d, J = 3.4 Hz, 1H), 2.96 (s, 6H). 727.3 0.394 479

1H NMR (400 MHz, DMSO-d6) δ 8.85-8.74 (m, 2H), 8.62 (d, J = 8.6 Hz, 1H),7.99 (s, 1H), 7.61 (dt, J = 8.8, 4.5 Hz, 1H), 7.54 (t, J = 7.2 Hz, 1H),7.36 (dd, J = 10.4, 7.3 Hz, 1H), 6.76 (t, J = 8.6 Hz, 1H), 6.44 (dd, J =11.4, 6.3 Hz, 2H), 4.75-4.56 (m, 1H), 4.31 (s, 1H), 3.88-3.79 (m, 4H),3.68 (ddd, J = 44.6, 14.4, 4.7 Hz, 1H), 3.35 (m, 1H), 1.90 (t, J = 1.3Hz, 3H), 1.77 (t, J = 10.1 Hz, 1H), 1.64-1.41 (m, 1H), 0.93 (t, J = 7.3Hz, 3H). 671.2 1.188 480

1H NMR (400 MHz, DMSO-d6) δ 8.89-8.60 (m, 3H), 7.73-7.55 (m, 2H), 7.46(d, J = 7.0 Hz, 1H), 6.56 (s, 1H), 6.32 (d, J = 12.2 Hz, 2H), 4.77-4.61(m, 3H), 3.78-3.64 (m, 2H), 3.59 (d, J = 7.5 Hz, 1H), 3.49 (d, J = 1.8Hz, 3H), 3.48-3.38 (m, 1H), 3.00 (d, J = 9.7 Hz, 1H), 2.54 (s, 3H),1.94-1.87 (m, 1H), 1.84 (d, J = 9.9 Hz, 1H). 643.2 0.297 481

1H NMR (400 MHz, DMSO-d6) δ 12.93 (s, 1H), 8.93 (dd, J = 4.4, 1.5 Hz,1H), 8.81 (dd, J = 8.3, 3.0 Hz, 2H), 7.77-7.69 (m, 2H), 7.62 (d, J = 7.4Hz, 1H), 7.52 (d, J = 3.3 Hz, 1H), 7.38 (d, J = 3.3 Hz, 1H), 6.78 (d, J= 9.4 Hz, 1H), 6.45 (d, J = 11.5 Hz, 2H), 4.67 (ddd, J = 9.8, 7.9, 4.6Hz, 1H), 4.31 (d, J = 9.2 Hz, 1H), 3.74 (d, J = 4.7 Hz, 1H), 3.71 (s,3H), 3.49 (s, 3H), 3.43 (dd, J = 14.5, 9.8 Hz, 1H), 1.77 (ddq, J = 11.6,7.5, 4.3, 3.8 Hz, 1H), 1.53 (ddt, J = 17.5, 14.3, 7.2 Hz, 1H), 0.93 (t,J = 7.3 Hz, 3H). 619.3 1.483 482

1H NMR (400 MHz, DMSO-d6) δ 9.39 (s, 1H), 9.34 (d, J = 9.2 Hz, 1H), 8.88(s, 1H), 8.83-8.76 (m, 2H), 8.13 (d, J = 6.7 Hz, 1H), 7.96 (d, J = 7.7Hz, 1H), 6.69- 6.57 (m, 2H), 4.83 (ddt, J = 16.3, 8.2, 3.9 Hz, 2H), 4.14(d, J = 12.6 Hz, 1H), 3.97-3.82 (m, 2H), 3.71 (d, J = 12.9 Hz, 1H),3.59-3.54 (m, 1H), 3.31 (s, 1H), 3.24 (d, J = 13.4 Hz, 2H), 2.67 (s,3H), 2.40 (s, 3H), 2.01 (s, 3H). 612.3 1.496 483

1H NMR (400 MHz, DMSO-d6) δ 12.98 (s, 1H), 8.96 (dd, J = 8.0, 5.0 Hz,1H), 8.85 (dd, J = 4.3, 1.5 Hz, 1H), 8.70 (d, J = 7.8 Hz, 1H), 7.72-7.63(m, 1H), 7.59 (t, J = 7.7 Hz, 1H), 7.47 (dd, J = 7.3, 4.9 Hz, 1H),6.59-6.49 (m, 3H), 5.02 (p, J = 5.7 Hz, 1H), 4.72 (dddd, J = 10.0, 7.4,4.5, 2.2 Hz, 1H), 3.80-3.74 (m, 1H), 3.74-3.65 (m, 1H), 3.49 (d, J = 2.5Hz, 3H), 3.48-3.36 (m, 2H), 2.54 (s, 3H), 2.07-1.98 (m, 1H), 1.90 (dq, J= 13.1, 7.8, 6.1 Hz, 1H), 0.88 (td, J = 8.1, 5.1 Hz, 1H), 0.79 (s, 1H).695.3 0.544 484

1H NMR (400 MHz, DMSO-d6) δ 8.99 (d, J = 7.9 Hz, 1H), 8.85 (d, J = 4.2Hz, 1H), 8.73 (d, J = 8.6 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.81 (d, J= 7.2 Hz, 1H), 7.75- 7.62 (m, 4H), 7.44 (t, J = 7.5 Hz, 1H), 6.78 (d, J= 11.8 Hz, 2H), 4.97-4.86 (m, 1H), 4.75-4.67 (m, 1H), 4.16 (d, J = 12.7Hz, 1H), 4.00-3.90 (m, 1H), 3.80- 3.71 (m, 2H), 3.69 (s, 3H), 3.61- 3.40(m, 3H), 3.31-3.18 (m, 1H). 668.2 0.143 485

1H NMR (400 MHz, DMSO-d6) δ 9.03 (d, J = 7.7 Hz, 1H), 8.79 (d, J = 4.1Hz, 1H), 8.55 (d, J = 8.6 Hz, 1H), 7.58 (dd, J = 8.7, 4.2 Hz, 1H), 7.52(d, J = 7.3 Hz, 1H), 7.40 (d, J = 7.2 Hz, 1H), 6.60- 6.45 (m, 3H),4.86-4.69 (m, 2H), 3.67 (dd, J = 14.5, 5.5 Hz, 1H), 3.63-3.55 (m, 1H),3.52- 3.40 (m, 4H), 3.19 (q, J = 8.7 Hz, 1H), 2.52 (s, 3H), 2.17-1.96(m, 4H). 683.3 0.233 486

1H NMR (400 MHz, DMSO-d6) δ 9.01 (d, J = 8.0 Hz, 1H), 8.80 (d, J = 4.2Hz, 1H), 8.60 (d, J = 8.5 Hz, 1H), 7.60 (m, 1H), 7.55 (d, J = 7.3 Hz,1H), 7.41 (d, J = 7.2 Hz, 1H), 6.83 (d, J = 11.5 Hz, 2H), 6.53 (s, 1H),5.37 (s, 1H), 4.70 (m, 1H), 3.83-3.91 (m, 4H), 3.73 (dd, J = 14.5, 4.1Hz, 1H), 3.48 (s, 3H), 3.44-3.35 (m, 1H), 3.32 (s, 1H), 2.83 (bs, 3H),2.53 (s, 3). 712.2 1.307 487

1H NMR (400 MHz, DMSO-d6) δ 9.04 (s, 1H), 8.99 (d, J = 7.7 Hz, 1H), 8.84(dd, J = 4.1, 1.5 Hz, 1H), 8.64 (dd, J = 8.6, 1.6 Hz, 1H), 8.60 (d, J =4.9 Hz, 1H), 7.91 (dd, J = 4.9, 0.7 Hz, 1H), 7.75 (d, J = 7.6 Hz, 1H),7.69- 7.63 (m, 2H), 6.76-6.63 (m, 2H), 4.90-4.74 (m, 2H), 4.19- 4.06 (m,3H), 3.95 (dd, J = 11.4, 3.6 Hz, 1H), 3.78-3.67 (m, 2H), 3.65 (s, 3H),3.61-3.46 (m, 2H), 3.37 (s, 1H), 3.31-3.18 (m, 1H), 2.07 (s, 3H), 1.16(t, J = 7.1 Hz, 3H). 709.2 NA 488

1H NMR (400 MHz, DMSO-d6) δ 9.04 (s, 1H), 8.99 (d, J = 7.7 Hz, 1H), 8.84(dd, J = 4.2, 1.5 Hz, 1H), 8.64 (dd, J = 8.7, 1.6 Hz, 1H), 8.60 (d, J =5.0 Hz, 1H), 7.91 (d, J = 4.9 Hz, 1H), 7.75 (d, J = 7.5 Hz, 1H),7.69-7.63 (m, 2H), 6.75-6.62 (m, 2H), 4.91- 4.75 (m, 2H), 4.20-4.07 (m,3H), 3.95 (dd, J = 11.4, 3.6 Hz, 1H), 3.78-3.67 (m, 2H), 3.66 (s, 3H),3.60-3.47 (m, 2H), 3.36 (d, J = 12.3 Hz, 1H), 3.25 (t, J = 12.3 Hz, 1H),2.07 (s, 3H), 1.16 (t, J = 7.1 Hz, 3H). 709.2 NA 489

1H NMR (400 MHz, DMSO-d6) δ 8.99 (d, J = 7.6 Hz, 1H), 8.87 (s, 1H), 8.62(d, J = 8.4 Hz, 1H), 7.67 (s, 1H), 7.61 (s, 2H), 6.70 (d, J = 13.0 Hz,1H), 6.66 (s, 1H), 4.89-4.77 (m, 2H), 4.76- 4.61 (m, 2H), 4.18-4.12 (m,1H), 3.93 (s, 1H), 3.87-3.79 (m, 2H), 3.73 (d, J = 12.9 Hz, 2H), 3.67(s, 4H), 3.60-3.46 (m, 2H), 3.35 (d, J = 9.6 Hz, 1H), 3.37 (m, 1H), 3.25(s, 4H), 2.37 (d, J = 10.2 Hz, 3H), 2.05 (s, 3H). 700.2 NA 490

1H NMR (400 MHz, DMSO-d6) δ 9.15 (d, J = 7.5 Hz, 1H), 8.85 (d, J = 4.2Hz, 1H), 8.65 (d, J = 8.6 Hz, 1H), 8.00 (t, J = 9.2 Hz, 1H), 7.80 (dd, J= 12.3, 6.4 Hz, 1H), 7.74 (d, J = 7.5 Hz, 1H), 7.69- 7.60 (m, 2H), 6.79(d, J = 11.8 Hz, 2H), 5.01-4.86 (m, 1H), 4.76 (q, J = 7.9 Hz, 1H), 4.17(d, J = 12.7 Hz, 1H), 3.96 (dd, J = 11.9, 3.6 Hz, 1H), 3.80-3.67 (m,2H), 3.64 (s, 3H), 3.58 (s, 1H), 3.55 (s, 3H), 3.44 (d, J = 12.9 Hz,1H), 3.24 (t, J = 12.4 Hz, 1H), 2.53 (s, 1H). 733.7 NA 491

1H NMR (400 MHz, DMSO-d6) δ 9.00 (d, J = 7.7 Hz, 1H), 8.85 (d, J = 4.1Hz, 1H), 8.67 (d, J = 8.6 Hz 1H), 8.34-8.30 (m, 1H), 7.75 (d, J = 7.5Hz, 1H), 7.71- 7.63 (m, 2H), 7.46-7.42 (m, 1H), 6.74-6.64 (m, 2H), 4.90-4.78 (m, 3H), 4.14 (d, J = 12.6 Hz, 1H), 4.06 (s, 3H), 3.95 (d, J = 11.7Hz, 1H), 3.79-3.65 (m, 5H), 3.62-3.47 (m, 6H), 3.34 (d, 1H), 3.25 (t, J= 12.6 Hz, 1H), 2.05 (s, 3H). 725.8 NA 492

1H NMR (400 MHz, DMSO-d6) δ 9.00 (d, J = 7.7 Hz, 1H), 8.90 (s, 1H), 8.84(d, J = 4.2 Hz, 1H), 8.66 (d, J = 8.6 Hz, 1H), 7.80- 7.73 (m, 2H), 7.67(t, J = 6.7 Hz, 2H), 6.75-6.61 (m, 2H), 4.84 (d, J = 10.4 Hz, 2H), 4.15(d, J = 12.7 Hz, 1H), 3.99-3.89 (m, 1H), 3.77-3.70 (m, 2H), 3.68 (s,2H), 3.63 (t, J = 1.7 Hz, 3H), 3.53 (dt, J = 14.6, 9.9 Hz, 2H), 3.34 (s,1H), 2.59 (s, 3H), 2.05 (s, 3H). 709.6 NA 493

1H NMR (400 MHz, DMSO-d6) δ 9.26-9.06 (m, 2H), 8.88 (d, J = 6.8 Hz, 2H),8.68 (d, J = 8.7 Hz, 1H), 7.78 (d, J = 7.6 Hz, 1H), 7.67 (t, J = 8.3 Hz,3H), 6.79 (d, J = 12.1 Hz, 2H), 4.92 (d, J = 9.3 Hz, 1H), 4.78 (q, J =7.7 Hz, 1H), 4.17 (d, J = 12.7 Hz, 1H), 3.94 (s, 2H), 3.65 (s, 3H), 3.58(m, 4H), 3.44 (d, J = 12.9 Hz, 1H), 3.26 (d, J = 12.7 Hz, 1H). 699.8 NA494

1H NMR (400 MHz, DMSO-d6) δ 9.15 (d, J = 7.5 Hz, 1H), 9.05 (s, 1H), 8.86(d, J = 4.2 Hz, 1H), 8.64 (dd, J = 28.6, 6.8 Hz, 2H), 7.91 (dd, J = 4.9,1.9 Hz, 1H), 7.77 (d, J = 7.5 Hz, 1H), 7.72- 7.55 (m, 2H), 6.79 (d, J =11.8 Hz, 2H), 4.96-4.82 (m, 1H), 4.77 (q, J = 8.0 Hz, 1H), 4.17 (d, J =12.7 Hz, 1H), 3.96 (dd, J = 11.6, 3.6 Hz, 1H), 3.82-3.68 (m, 2H), 3.56(dd, J = 14.0, 9.9 Hz, 2H), 3.44 (d, J = 13.3 Hz, 1H), 3.24 (t, J = 12.0Hz, 1H) 699.2 NA 495

1H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 9.11 (d, J = 7.7 Hz, 1H),8.86 (dd, J = 4.2, 1.6 Hz, 1H), 8.65 (dd, J = 8.7, 1.6 Hz, 1H),7.69-7.54 (m, 3H), 7.34 (s, 1H), 6.78 (d, J = 11.8 Hz, 2H), 4.97-4.86(m, 1H), 4.80-4.69 (m, 1H), 4.31 (d, J = 14.6 Hz, 1H), 4.21-4.06 (m,2H), 3.96 (dd, J = 11.6, 3.8 Hz, 1H), 3.81-3.70 (m, 2H), 3.70- 3.64 (m,3H), 3.61-3.35 (m, 9H), 3.30-3.08 (m, 2H), 2.97 (s, 3H). 700.3 NA 496

1H NMR (400 MHz, DMSO-d6) δ 9.11 (d, J = 7.4 Hz, 3H), 8.85 (t, J = 3.1Hz, 1H), 8.63 (d, J = 8.6 1H), 7.60 (dtd, J = 23.9, 7.6, 2.8 Hz, 3H),7.36 (d, J = 2.4 Hz, 1H), 6.78 (d, J = 12.3 Hz, 2H), 4.91 (d, J = 9.3Hz, 1H), 4.74 (q, J = 7.8 Hz, 1H), 4.17 (d, J = 12.7 Hz, 2H), 3.96 (d, J= 11.7 Hz, 1H), 3.79-3.62 (m, 5H), 3.61- 3.38 (m, 8H), 3.24 (t, J = 12.6Hz, 1H), 3.07 (d, J = 6.3 Hz, 2H). 686.4 NA

α4β1 Cell Capture Assay

The potency of inhibitors in preventing α4β1 integrin interaction withVCAM-1 was measured by monitoring the capture of α4β1 expressing cellsto a recombinant VCAM-1 extracellular domain-coated plate.

384-well plates (Corning 3702) were coated with VCAM-1 extracellulardomain by dispensing 20 μL of VCAM-1 at 0.5 μg/ml per well andincubating overnight at 4° C. The plates were then washed with PBS andblocked with 3% BSA for 2 hours before being washed again.

Jurkat cells were spun down and re-suspended in assay medium (DMEM+0.5%FBS+0.5 mM MnCl₂) at a density of 0.5×106 cells/ml. The cells were thendispensed (60 μL/well) to a 384-well plate (Greiner 781280) that waspreviously spotted with 60 nL of test compound per well. The plates wereincubated at 37° C. for 1 hour. 50 μL of cells were transferred to theblocked, VCAM-1-coated plates and incubated for 30 minutes at 37° C. 10μL of 12% glutaraldehyde containing Hoechst 33342 (0.06 mg/mL) was addedto the cells (2% glutaraldehyde and 0.01 mg/mL Hoechst 33342 finalconcentrations). The plates were incubated for 90 minutes at roomtemperature. The plates were then washed 3 times with 70 μL of PBS perwell and imaged on a Cellomics ArrayScan instrument. The cells that werebound to the plate were counted and plotted against the compoundconcentration to determine the EC50 of the test compounds.

The parent carboxylic acids in Table 3 display at least 70 foldsselectivity over α4β1, as calculated from the ratio of EC50 values incell capture assays for α4β1 and α4β7. These assays measure the captureof α4β1 or α4β7 expressing cells by a recombinant VCAM-1 or MadCAM-1extracellular domain-coated plate, respectively.

Dog Bioavailability Experiments

Pharmacokinetic studies for were performed in non-naïve male beagle dogs(three animals per dosing route) following federal and InstitutionalAnimal Care and Use Committee in humans (IACUC) guidelines. Intravenous(iv) administration was dosed via infusion over 30 minutes. Theintravenous dose for dogs was formulated in a sterile solution. Onesolution formulation was 20% polyethylene glycol 300 and 80% water, pH8-9. Oral dosing in dogs was administered by gavage as a solution. Oneformulation for dog was 72% 10 mM HCl, 5% N-methylpyrrolidone, 20%polyethylene glycol 200, and 3% Vitamin E TPGS, pH 2-3. Blood sampleswere collected over a 24 h period post-dose, plasma was isolated, andthe concentration of the test compound in plasma was determined withLC/MS/MS after protein precipitation with acetonitrile.Non-compartmental pharmacokinetic analysis was performed on the plasmaconcentration-time data.

Bioavailability (% F) is defined as the area under theconcentration/time curve (AUC) of parent carboxylic acid in systemiccirculation following oral administration of ester prodrug divided bythe AUC of amount of parent carboxylic acid in circulation followingintravenous administration of the parent carboxylic acid, normalized tothe same dose. Results for dog oral bioavailability are presented inTable 4.

TABLE 4 Prodrug Parent carboxylic Example % F acid 346 5 Example 91 34711 Example 91 348 3 Example 91 349 9 Example 91 351 35 Example 91 355 18Example 356 357 9 Example 356 358 2 Example 356 359 12 Example 356 36037 Example 356 361 5 Example 356 363 37 Example 356 364 3 Example 356365 16 Example 356 368 8 Example 356 487 20 Example 408 494 8 Example474

1. (canceled)
 2. A compound of formula (II):

or a pharmaceutically acceptable salt thereof, wherein: L is selectedfrom a bond, —O—, —O—C(O)—*, —NH—, —C(O)—N(H)—*, and —N(H)—C(O)—*;wherein * indicates the point of attachment of L to R¹; R¹ is selectedfrom A¹, A², and A³; A¹ is 5-10 membered heteroaryl containing one tofive heteroatoms independently selected from S, N, and O; wherein A¹optionally comprises one to three C(O); and wherein A¹ is optionallysubstituted with one to six R^(a); A² is C₆₋₁₀aryl, optionallysubstituted with one to six R^(a); and A³ is C₅₋₁₀cycloalkyl or 5-14membered heterocyclyl; wherein A³ is optionally substituted with one tofour groups independently selected from oxo and R^(a); wherein eachR^(a) is independently selected from halo, cyano, hydroxyl,—NR^(a1)R^(a2), C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxyl,C₁₋₆haloalkyl, C₁₋₆haloalkoxyl, —S(O)_(m)—C₁₋₆alkyl, C₃₋₆cycloalkyl, 3-6membered heterocyclyl, C₆₋₁₀aryl, 5-6 membered heteroaryl,—O—C₃₋₆cycloalkyl, —O-(3-6 membered heterocyclyl),—O—C₁₋₄alkylene-C₃₋₈cycloalkyl, and —O-phenyl; wherein eachC₃₋₈cycloalkyl, 3-6 membered heterocyclyl, C₆₋₁₀aryl, 5-6 memberedheteroaryl, —O—C₃₋₈cycloalkyl, —O-(3-6 membered heterocyclyl), —O—C₁₋₄alkylene-C₃₋₈cycloalkyl, and —O-phenyl of R^(a) is independentlyoptionally substituted with one to three groups independently selectedfrom halo, cyano, hydroxyl, —NR^(a1)R^(a2), C₁₋₆alkyl, C₁₋₆haloalkyl,C₁₋₆alkoxyl, and C₁₋₆haloalkoxyl; and wherein each C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxyl, C₁₋₆haloalkyl, C₁₋₆haloalkoxyl,and —S(O)_(m)—C₁₋₆alkyl of R^(a) is optionally substituted with one tothree R^(a3), wherein each R^(a3) is independently selected from halo,cyano, hydroxyl, —NR^(a1)R^(a2), C₁₋₆alkoxyl, C₃₋₈cycloalkyl, and 3-6membered heterocyclyl; wherein each C₃₋₈cycloalkyl and 3-6 memberedheterocyclyl of R^(a3) is optionally substituted with one to threeR^(a4); and each R^(a4) is independently selected from halo, cyano,hydroxyl, —NR^(a1)R^(a2), C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxyl,C₁₋₆haloalkoxyl, C₃₋₈cycloalkyl, and 3-6 membered heterocyclyl; each R²,R³, R⁴, R⁵, and R⁶ is independently selected from H, halo, cyano,hydroxyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxyl,C₁₋₈haloalkyl, C₁₋₈haloalkoxyl, —NR^(b1)R^(b2), —R^(b3)S(O)_(m)R^(b4),—S(O)_(m)R^(b4), —NR^(b1)S(O)_(n)R^(b4), —COOR^(b1), —CONR^(b1)R^(b2),—NR^(b1)COOR^(b2), —NR^(b1)COR^(b4), —R^(b3)NR^(b1)R^(b2),—S(O)_(n)NR^(b1)R^(b2), C₃₋₁₂cycloalkyl, C₆₋₁₀aryl, 5-6 memberedheteroaryl, and 3-12 membered heterocyclyl; wherein each C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxyl, C₁₋₈haloalkyl, andC₁₋₈haloalkoxyl of R², R³, R⁴, R⁵, and R⁶ is optionally substituted withone to two R^(c); wherein each R^(c) is independently selected fromazido, oxo, cyano, halo, hydroxyl, —NR^(a1)R^(a2), C₁₋₄alkoxyl,C₃₋₈cycloalkyl, C₆₋₁₀aryl, 5-6 membered heteroaryl, and 4-6 memberedheterocyclyl; wherein each C₃₋₈cycloalkyl, C₆₋₁₀aryl, 5-6 memberedheteroaryl, and 4-6 membered heterocyclyl of R^(c) is optionallysubstituted with one to three groups independently selected from halo,cyano, hydroxyl, —NR^(a1)R^(a2), C₁₋₄alkyl, C₁₋₆haloalkyl, C₁₋₄alkoxyl,and C₃₋₆cycloalkyl; wherein each C₆₋₁₀aryl, and 5-6 membered heteroarylof R², R³, R⁴, R⁵, and R⁶ is independently optionally substituted withone to five R^(b); and wherein each C₃₋₁₂cycloalkyl, and 3-12 memberedheterocyclyl of R², R³, R⁴, R⁵, and R⁶ is independently optionallysubstituted one to six groups independently selected from ═CR^(b1)R^(b2)and R^(b); wherein each R^(b) is independently selected from azido,cyano, halo, hydroxyl, —NR^(a1)R^(a2), C₁₋₆alkyl, C₁₋₈haloalkyl,C₁₋₆alkoxyl, C₃₋₆cycloalkyl, C₆₋₁₀aryl, 5-6 membered heteroaryl, and 4-6membered heterocyclyl; wherein each C₃₋₆cycloalkyl, C₆₋₁₀aryl, 5-6membered heteroaryl, and 4-6 membered heterocyclyl of R^(b) isindependently optionally substituted with one to three groupsindependently selected from halo, cyano, hydroxyl, —NR^(a1)R^(a2),C₁₋₄alkyl, C₁₋₄haloalkyl, and C₁₋₄alkoxyl;  wherein each R^(b1) andR^(b2) is independently selected from H, C₁₋₆alkyl, C₁₋₈haloalkyl,C₃₋₈cycloalkyl, C₆₋₁₀aryl, 5-6 membered heteroaryl, and 3-8 memberedheterocyclyl;  wherein each C₃₋₈cycloalkyl, C₆₋₁₀aryl, 5-6 memberedheteroaryl, and 4-6 membered heterocyclyl of R^(b1) and R^(b2) isindependently optionally substituted with one to three groupsindependently selected from halo, cyano, hydroxyl, —NR^(a1)R^(a2),C₁₋₈alkyl, C₁₋₈haloalkyl, C₁₋₆alkoxyl, C₃₋₆cycloalkyl, C₆₋₁₀aryl, 5-6membered heteroaryl, and 4-6 membered heterocyclyl; and  wherein eachC₁₋₆alkyl and C₁₋₈haloalkyl of R^(b1) and R^(b2) is optionallysubstituted with one to two R^(b5);  wherein R^(b3) is C₁₋₄alkylene; wherein R^(b4) is selected from C₁₋₄alkyl, C₁₋₄haloalkyl,C₃₋₆cycloalkyl, C₆₋₁₀aryl, 5-6 membered heteroaryl, and 4-6 memberedheterocyclyl; wherein each C₁₋₄alkyl, C₁₋₄haloalkyl, C₃₋₈cycloalkyl,C₆₋₁₀aryl, 5-6 membered heteroaryl, and the 4-6 membered heterocyclyl ofR^(b4) is optionally substituted with one to three R^(b6);  wherein eachR^(b5) is independently selected from cyano, hydroxyl, C₁₋₄ alkoxyl,C₃₋₈cycloalkyl, C₆₋₁₀aryl, 5-6 membered heteroaryl, and 4-6 memberedheterocyclyl; and each C₁₋₄alkoxyl, C₃₋₈cycloalkyl, C₆₋₁₀aryl, 5-6membered heteroaryl, and 4-6 membered heterocyclyl of R^(b5) isoptionally substituted with one to three groups independently selectedfrom halo, cyano, hydroxyl, —NR^(a1)R^(a2), C₁₋₄ alkyl, C₁₋₄haloalkyl,C₁₋₄alkoxyl, and phenyl; and  wherein each R^(b6) is independentlyselected from halo, cyano, C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxyl,C₃₋₆cycloalkyl, phenyl, 4-6 membered heterocyclyl, and 5-6 memberedheteroaryl; wherein each C₃₋₆cycloalkyl, 4-6 membered heterocyclyl, and5-6 membered heteroaryl of R^(b6) is independently optionallysubstituted with one to three groups independently selected from halo,cyano, —NR^(a1)R^(a2), C₁₋₄alkyl, C₁₋₄ haloalkyl, and C₁₋₄alkoxyl; or R²and R³, R³ and R⁴, or R⁵ and R⁶ together with the atoms to which theyare attached form a C₆₋₁₀aryl, 5-6 membered heteroaryl, C₃₋₆cycloalkyl,or 5-6 membered heterocyclyl; wherein each C₆₋₁₀aryl, 5-6 memberedheteroaryl, C₃₋₆cycloalkyl, and 5-6 membered heterocyclyl isindependently optionally substituted with one to three groupsindependently selected from halo, cyano, —NR^(a1)R^(a2), C₁₋₆alkyl,C₁₋₆alkoxyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, 3-6 membered heterocyclyl,C₆₋₁₀aryl, 5-6 membered heteroaryl, C₁₋₄alkylene-C₃₋₈cycloalkyl,C₁₋₄alkylene-C₆₋₁₀ aryl, and C₁₋₄alkylene-(5-6 membered heteroaryl);each R⁷, R⁸, R⁹, R¹⁰, and R¹¹ is independently selected from H, halo,hydroxyl, cyano, C₁₋₆ alkyl, C₁₋₆alkoxyl, C₁₋₆haloalkyl,C₁₋₆haloalkoxyl, and —NR^(a1)R^(a2); R¹³ is selected from H, C₁₋₄alkyl,and C₁₋₄haloalkyl; and R¹⁴ is selected from H, C₁₋₆alkyl,—C₁₋₄alkylene-NR^(a1)R^(a2), —C₁₋₄alkylene-C(O)NR^(a1)R^(a2),—C₁₋₄alkylene-O—C(O)—C₁₋₄alkyl, —C₁₋₄alkylene-O—C(O)—O—C₁₋₄alkyl,—C₁₋₄alkylene-O—C(O)—C₁₋₄alkylene-NR^(a1)R^(a2),—C₁₋₄alkylene-O—C₁₋₄alkyl, C₃₋₈cycloalkyl, —C₁₋₄alkylene-C₃₋₈cycloalkyl,4-6 membered heterocyclyl, and —C₁₋₄alkylene-(4-6 memberedheterocyclyl); wherein each C₃₋₈cycloalkyl,—C₁₋₄alkylene-C₃₋₈cycloalkyl, 4-6 membered heterocyclyl, and—C₁₋₄alkylene-(4-6 membered heterocyclyl) of R¹⁴ is optionallysubstituted with one to three groups independently selected from halo,C₁₋₄alkyl, C₁₋₄alkoxyl, and C₁₋₄haloalkyl; or R¹⁴ together with the Nthat attaches to R¹³ forms a 5 membered heterocyclyl; wherein the 5membered heterocyclyl is optionally substituted with one to two groupsindependently selected from halo, C₁₋₆alkyl, C₁₋₆alkoxyl, C₁₋₆haloalkyl,and C₆₋₁₀aryl; wherein the C₆₋₁₀aryl is optionally substituted with oneto three groups independently selected from halo, C₁₋₆alkyl,C₁₋₆alkoxyl, C₁₋₆haloalkyl; each R^(a1) and R^(a2) is independentlyselected from H, C₁₋₆alkyl, and C₁₋₆haloalkyl; m is selected from 0, 1,and 2; and n is selected from 1, and
 2. 3-39. (canceled)
 40. Thecompound of claim 2, or a pharmaceutically acceptable salt thereof,wherein the compound is selected from:

41-57. (canceled)
 58. The compound of claim 2, or a pharmaceuticallyacceptable salt thereof, wherein the compound is of formula (Jd):

wherein R^(z) is selected from H, —CH₃, —CD₃, —CH₂F, —CHF₂, —CF₃, and—CH₂CH₃; X¹ is selected from CR^(x1), and N; X² is selected fromCR^(x1)R^(x2), NR^(x2), O, and S(O)₂; wherein R^(x1) is selected from H,and R^(b); and R^(x2) is selected from H, C₁₋₄alkyl, and C₁₋₄haloalkyl;q is selected from 0, 1, 2, and 3; and r is selected from 0, 1, 2, and3. 59-61. (canceled)
 62. The compound of claim 2, or a pharmaceuticallyacceptable salt thereof; wherein R¹ is


63. The compound of claim 2, or a pharmaceutically acceptable saltthereof; wherein R³ and R⁵ are H. 64-65. (canceled)
 66. The compound ofclaim 2, or a pharmaceutically acceptable salt thereof, wherein each R²and R⁶ is independently selected from F and —CH₃. 67-70. (canceled) 71.The compound of claim 2, or a pharmaceutically acceptable salt thereof,wherein R⁴ is

substituted with —CF₃. 72-80. (canceled)
 81. The compound of claim 2, ora pharmaceutically acceptable salt thereof, wherein R¹⁴ is selected fromH, methyl, and ethyl. 82-86. (canceled)
 87. The compound of claim 2, ora pharmaceutically acceptable salt thereof, wherein the compound isselected from:

88-99. (canceled)
 100. A compound, or a pharmaceutically acceptable saltthereof, wherein the compound is


101. A compound, or a pharmaceutically acceptable salt thereof, whereinthe compound is


102. The compound of claim 2, or a pharmaceutically acceptable saltthereof, wherein the compound is


103. The compound of claim 2, or a pharmaceutically acceptable saltthereof, wherein the compound is


104. A pharmaceutical composition comprising the compound of claim 100,or a pharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable carrier.
 105. The pharmaceutical compositionof claim 104, further comprising at least one or more additionaltherapeutic agents.
 106. The pharmaceutical composition of claim 105,wherein the at least one or more additional therapeutic agents areindependently selected from JAK tyrosine kinase inhibitors, TumorProgression Locus 2 (TPL2) inhibitors, and IRAK4 inhibitors.
 107. Thepharmaceutical composition of claim 106, wherein the additionaltherapeutic agent is a JAK tyrosine kinase inhibitor, and wherein theJAK tyrosine kinase inhibitor is Filgotinib.
 108. A method for treatingan inflammatory disease or condition associated with α4β7 integrincomprising administrating to a subject an effective amount of thecompound of claim 100, or a pharmaceutically acceptable salt thereof.109. The method of claim 108, wherein the inflammatory disease orcondition is selected from inflammatory bowel disease (IBD), Ulcerativecolitis, Crohn's disease, graft-versus-host disease (GVHD), and primarysclerosing cholangitis (PSC).
 110. A pharmaceutical compositioncomprising the compound of claim 101, or a pharmaceutically acceptablesalt thereof, and at least one pharmaceutically acceptable carrier. 111.The pharmaceutical composition of claim 110, further comprising at leastone or more additional therapeutic agents.
 112. The pharmaceuticalcomposition of claim 111, wherein the at least one or more additionaltherapeutic agents are independently selected from JAK tyrosine kinaseinhibitors, TPL2 inhibitors, and IRAK4 inhibitors.
 113. Thepharmaceutical composition of claim 112, wherein the additionaltherapeutic agent is a JAK tyrosine kinase inhibitor, and wherein theJAK tyrosine kinase inhibitor is Filgotinib.
 114. A method for treatingan inflammatory disease or condition associated with α4β7 integrincomprising administrating to a subject an effective amount of thecompound of claim 101, or a pharmaceutically acceptable salt thereof.115. The method of claim 114, wherein the inflammatory disease orcondition is selected from inflammatory bowel disease (IBD), Ulcerativecolitis, Crohn's disease, graft-versus-host disease (GVHD), and primarysclerosing cholangitis (PSC).